RU2733393C9 - Compounds for treating cancer - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: present invention relates to a compound of formula II, where Q is NH; Z is CH or N; A is phenyl, indolyl or indazolyl, each of which is optionally substituted with at least one of the following: C₁-C₅ linear or branched alkyl or a combination thereof; R₁ independently represents hydrogen, O-(C₁-C₅)alkyl, O-halogen(C₁-C₅)alkyl, halogen(C₁-C₅)alkyl, -O(CH₂)_jOCH₃, -O(CH₂)_jNHCH₃, -O(CH₂)_jNH₂, -O-(CH₂)_jN(CH₃)₂, - OC(O)CF₃, -OC(O)CH₂Cl, -OCH₂Ph, -O(CH₂)_jN-phthalimide or a combination thereof; R₂ is hydrogen, O-(C₁-C₅)alkyl, O-halogen(C₁-C₅)alkyl, F, Cl, Br, I, halogen(C₁-C₅)alkyl, CN, NO₂, -CH₂CN, NH₂, hydroxyl, COOH, C(O)H, NHCO-(C₁-C₅)alkyl, -O(CH₂)_kOCH₃, -O(CH₂)_kOH, -O(CH₂)_kNHCH₃, -O(CH₂)_kNH₂, -O-(CH₂)_kN(CH₃)₂, -OC(O)CF₃, -OC(O)CH₂Cl, -OCH₂Ph and -O(CH₂)_kN-phthalimide; j and k independently represent integers from 1 to 5; n is integer from 1 to 4; or a hydrate thereof, a pharmaceutically acceptable salt or a combination thereof.

EFFECT: compounds of formula II have anti-cancer activity and are intended for treating, relieving, reducing severity, reducing the risk of developing or suppressing cancer.

23 cl, 12 dwg, 4 tbl, 6 ex

Description

Declaration of State Interest

The present invention was created in whole or in part with government support in the form of a professor position supported by the Van Vleet Professorship (D.D.M.) and NIH (National Institutes of Health) Grants R01CA148706, 1S10RR026337-01, 1S10OD010678-01 (W.L.). The US government has certain rights in this invention.

Technology area

The present invention relates to compounds that interact with the colchicine binding site having anticancer activity, to compositions containing said compounds and their use in the treatment of various forms of cancer.

State of the art

Cancer is the second most common cause of death in the United States, second only to heart disease. In the United States, cancer is the cause of 1 in 4 deaths. The 5-year relative survival rate for all cancer patients diagnosed between 1996 and 2003 is 66%, compared to 50% between 1975 and 1977 (Cancer Facts & Figures American Cancer Society: Atlanta, GA (2008)). This improvement in survival reflects advances in early diagnosis and the development of treatments. The main goal of cancer research is to identify highly effective anti-cancer agents with low toxicity.

Prostate cancer is one of the most commonly diagnosed non-cutaneous cancers in men in the United States and is the second most common cause of cancer death, with 180,000 new cases and nearly 29,000 deaths expected this year. Patients with advanced prostate cancer receive antiandrogen therapy (ADT), usually with luteinizing hormone releasing hormone (LHF) agonists or bilateral orchiectomy. Antiandrogen therapy lowers not only testosterone levels, but also estrogen levels, since estrogen is produced by the aromatization of testosterone, which is reduced by ADT. Estrogen deficiency caused by antiandrogen therapy leads to significant side effects, including hot flashes, gynecomastia and mastalgia, bone loss, decreased bone quality and strength, osteoporosis and life-threatening fractures, irreversible lipid changes, increased risk of cardiovascular disease and myocardial infarction , depression and other mood changes.

Malignant melanoma is the most dangerous form of skin cancer and is responsible for approximately 75% of all skin cancer deaths. The number of cases of melanoma is gradually increasing among the population of the Western world. This number has doubled over the past 20 years. Approximately 160,000 new cases of melanoma are diagnosed annually around the world, most often in men and Caucasians. According to a WHO report, there are approximately 48,000 melanoma-related deaths worldwide every year.

Currently, there are no effective treatments for metastatic melanoma. Metastatic melanoma is highly resistant to existing methods of chemotherapy, radiotherapy and immunotherapy. Metastatic melanoma has a very poor prognosis: the median survival time is 6 months, and the 5-year survival rate is less than 5%. For the past 30 years, dacarbazine (DTIC) has been the only drug approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma. However, dacarbazine provides complete remission in only less than 5% of patients. In recent years, significant efforts have been made to combat metastatic melanoma. Combinations of DTIC with other chemotherapeutic drugs (eg, cisplatin, vinblastine, and carmustine) or the addition of interferon-α2b to DTIC did not provide an improvement in survival compared to treatment with DTIC alone. Recent clinical trials of antibodies and vaccines for the treatment of metastatic melanoma have also failed to achieve satisfactory efficacy. Ipilimumab (Yervoy) is a drug that activates a subject's immune system to combat melanoma. Ipilimumab is used to treat advanced melanoma that has spread beyond its original location. Targeted therapy uses drugs designed to target specific vulnerabilities in cancer cells. Vemurafenib (Zelboraf) is a targeted therapy approved for the treatment of advanced melanoma that does not respond to surgery, or melanoma that has spread throughout the body. Vemurafenib can only cure melanoma that has a specific genetic mutation.

Drugs that interact with tubulin / microtubules have been successfully used to treat a wide variety of human cancers. They are often classified into two main categories: drugs that stabilize microtubules (eg, taxanes, epothilones) and drugs that destabilize microtubules (eg, vinca alkaloids, colchicine). In the α, β-tubulin subunits, three main binding sites were identified: binding sites for taxanes, vinca alkaloids, and colchicine. Although antimitotic agents that interact with the taxane or vinca alkaloids in tubulin have very high efficacy in clinical oncology, there are currently no drugs that interact with the colchicine binding site that have been approved by the FDA. and US medicines for the treatment of cancer. Most colchicine binding agents have high potency, a chemical structure that is relatively easy to optimize, selective toxicity to the tumor vasculature, and have a promising ability to overcome multidrug resistance mediated by the P-glycoprotein (P-gp) efflux pump.

Some excellent agents for this approach are shown in Figure 1. Combretastatin A-4 (CA-4) is the most active member of the combretastatin family, isolated from the African tree Combretum caffrum. CA-4 has high antitubulin activity due to binding to the colchicine site and is the subject of phase II and III clinical trials. Replacement of the olefin bridge in CA-4 with a carbonyl group leads to the production of fenstatin, which has an activity and mechanism of action similar to CA-4. BPR0L075 and Oxi-6196 are 2-aroylindole and dihydronaphthalene analogs of CA-4 that provide potent inhibition of tubulin polymerization. Methylated chalcone SD400, which has an IC ₅₀ value for human K562 leukemia cells of 0.21 nM, is a highly potent tubulin inhibitor. Podophyllotoxin is a toxic non-alkaloid lignin and also has anti-cancer properties that can inhibit tubulin polymerization by binding to the colchicine binding site. Accordingly, compounds interacting with the colchicine binding site have been of great interest to specialists in the field of medicinal chemistry in recent years.

Brief description of the invention

In one embodiment, the present invention relates to a compound represented by Formula II:

where

Q is S, NH or O;

Z is CH or N;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₁ independently represents hydrogen, O-alkyl, O-haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O- (CH ₂ ) _j N (CH ₃ ) ₂ , - OC (O) CF ₃ , —OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _j NH ₂ , —O (CH ₂ ) _j N-phthalimide, or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O- (CH ₂ ) _k N (CH ₃ ) ₂ , -OC (O) CF ₃ , —OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _k NH ₂ or —O (CH ₂ ) _k N-phthalimide;

i, j and k are independently integers from 0 to 5;

n is an integer from 1 to 4;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound represented by Formula XII:

where

Q is S, NH or O;

X is a bond or NH;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _j NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₃ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _o NHCH ₃ , - (CH ₂ ) _o NH ₂ , - (CH ₂ ) _o N (CH ₃ ) ₂ , - O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , - SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C ( O) H or —C (O) NH ₂ ;

i and o independently represent integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a pharmaceutical composition according to the present invention. In another embodiment, the present invention relates to a pharmaceutical composition according to the present invention and at least one pharmaceutically active compound suitable for the treatment of cancer.

In one embodiment, the present invention provides a method of treating, ameliorating, reducing the severity, reducing the risk, or suppressing cancer, comprising administering a compound of the present invention to a subject with cancer under conditions that are effective for curing the cancer. In another embodiment, the cancer is selected from the group consisting of prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer, melanoma, drug-resistant melanoma, lung cancer , colon cancer, glioma, leukemia, lymphoma, kidney cancer, CNS cancer, uterine cancer, drug-resistant uterine cancer, and combinations thereof. In another embodiment, the administration of a compound of the present invention is in combination with another cancer therapy.

In one embodiment, the present invention provides a method for treating drug resistant tumor or tumors, comprising administering a compound of the present invention to a subject suffering from cancer under conditions that are effective to cure drug resistant tumor or tumors. In another embodiment, the cancer is selected from the group consisting of prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer, melanoma, drug-resistant melanoma, lung cancer , colon cancer, glioma, leukemia, lymphoma, kidney cancer, CNS cancer, uterine cancer, drug-resistant uterine cancer, and combinations thereof. In another embodiment, the administration of a compound of the present invention is in combination with another cancer therapy.

Other features and advantages of the present invention will become apparent from the following detailed description, examples and figures. It should be understood, however, that the detailed description and specific examples, although they indicate preferred embodiments according to the present invention, are given by way of illustration only, as various changes and modifications without departing from the spirit and scope of the invention will be apparent. specialists in the art after reading this detailed description.

Brief Description of Drawings

Figure 1 depicts the structures of typical tubulin inhibitors that bind to the colchicine binding site.

Figure 2 depicts a synthesis scheme for the preparation of compounds according to the present invention. Reagents and conditions: a) TsOH, EtOH, heating under reflux; b) (3,4,5-trimethoxyphenyl) boronic acid, K ₂ CO ₃ , Pd (PPh ₃ ) ₄ .

Figure 3 shows a synthesis scheme for the preparation of 4-substituted analogs of methoxybenzoyl-aryl-thiazole (SMART) aimed at modification at the para-position of the benzoyl ring. Reagents and conditions: (a) MeOH / phosphate buffer, pH = 6.4, RT; (b) EDCI, HOBt, NMM, CH ₃ OCH ₃ NH⋅HCl; (c) CBrCl ₃ , DBU; (d) 5-bromo-1,2,3-trimethoxybenzene / BuLi, THF, -78 ° C; (f) AlCl ₃ , CH ₂ Cl ₂ ; (f) ClCH ₂ COCl, CH ₂ Cl ₂ , NEt ₃ (12) or (CF ₃ CO) ₂ O, CH ₂ Cl ₂ , DMAP (13); (g) PhCH ₂ Br, K ₂ CO ₃ , DMF (14); MOMCl, Hünig base, CH ₂ Cl ₂ (15); BrCH ₂ CH ₂ NHBoc, DMF, Cs ₂ CO ₃ (16) or 2- (2-bromoethyl) isoindoline-1,3-dione, K ₂ CO ₃ , DMF, 120 ° C (17); (h) 4M HCl in dioxane.

Figure 4 depicts a synthesis scheme for the preparation of phenyl-amino-thiazole / imidazole analogs. Reagents and conditions: (a) BrCN, Et ₂ O / hexane; (b) CH ₃ SO ₃ H, EtOH, heating under reflux, 24 hours; (c) (1) 6M HCl, (2) NaOH 25% conc .; (d) PhSO ₂ Cl, Et ₃ N; (f) -78 ° C, t-BuLi, 3,4,5-trimethoxybenzoyl chloride; (f) Boc ₂ O, NaOH; (g) (chloromethanetriyl) tribenzene, Et ₃ N, CH ₂ Cl ₂ ; (h) HCl; (i) H ₂ , Pd — C, 5% EtOH, 40 psi (280 kPa); (j) PhCOSCN, Me ₂ CO; (k) MeOH, 1N. NaOH; (l) EtOH, 65 ° C; (m) NaOH, MeOH; (n) HBTU, NMM, HNCH ₃ OCH ₃ HCl, CH ₂ Cl ₂ ; (o) 3,4,5-trimethoxyphenyl bromide, n-BuLi, THF.

Figure 5 depicts tubulin irreversibly binding agents and possible interactions of Cys-241 at the para-position of the benzoyl ring in compounds of formula XI-XV.

Figure 6 depicts possible binding sites for compound 4 (tube model, Glidescore docking index -8.58) and 7 (tube model, Glidescore docking index -8.10) in α, β-tubulin dimer (PDB code: 1SA0) ... The natural ligand, DAMA-colchicine (Glidescore -9.26 docking index) is shown in the wire model.

Figure 7 shows possible binding sites for compound 33 (tube model, Glidescore docking index -8.70) and the natural ligand DAMA-colchicine (wire model, Glidescore docking index -9.26) in α, β-tubulin dimer (code PDB: 1SA0).

Figure 8 shows the putative metabolites and metabolic pathway of Compound 15.

Figure 9 shows the putative metabolites and metabolic pathway of Compound 18.

Figure 10 shows the putative metabolites and metabolic pathway of Compound 4.

Figure 11 shows the putative metabolites and metabolic pathway of Compound 7.

Figure 12 shows the in vitro inhibition of tubulin polymerization by compounds 4 and 7.

Detailed description of the invention

In one embodiment, the present invention relates to a compound of formula (I)

where

Q is S, NH or O;

Z is CH or N;

A represents substituted or unsubstituted systems of individual, fused or multiple aryl or (hetero) cyclic rings, including saturated and unsaturated N-heterocycles, saturated and unsaturated S-heterocycles and saturated and unsaturated O-heterocycles, saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated mixed heterocycles, aliphatic linear or branched C ₁ -C ₃₀ hydrocarbons;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R _{1 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H , NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O- (CH ₂ ) _j N (CH ₃ ) ₂ , - OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N- phthalimide or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O- (CH ₂ ) _k N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _k NH ₂ or -O (CH ₂ ) _k N-phthalimide ;

i, j and k are independently integers from 0 to 5;

n is an integer from 1 to 4;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, tautomer, polymorph, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (II)

where

Q is S, NH or O;

Z is CH or N;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _j NH ₂ , - (CH ₂ ) _j N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R _{1 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H , NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O- (CH ₂ ) _j N (CH ₃ ) ₂ , - OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N- phthalimide or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O- (CH ₂ ) _k N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _k NH ₂ or -O (CH ₂ ) _j N-phthalimide ;

i, j and k are independently an integer from 0 to 5;

n is an integer from 1 to 4;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (III)

where:

Z is CH or N;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _j NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R _{1 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H , NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N-phthalimide or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O (CH ₂ ) _k N (CH ₃ ) ₂ , —OC (O) CF ₃ , —OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _k NH ₂ or —O (CH ₂ ) _k N-phthalimide;

i, j and k are independently integers from 0 to 5;

n is an integer from 1 to 4;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (IV)

where

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R _{1 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H , NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _k N-phthalimide or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O (CH ₂ ) _k N (CH ₃ ) ₂ , —OC (O) CF ₃ , —OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _k NH ₂ or —O (CH ₂ ) _k N-phthalimide;

i, j and k are independently integers from 0 to 5;

n is an integer from 1 to 4;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (V)

where

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R _{1 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H , NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ , -O (CH ₂ ) _j N-phthalimide or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O (CH ₂ ) _k N (CH ₃ ) ₂ , —OC (O) CF ₃ , —OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _k NH ₂ or —O (CH ₂ ) _k N-phthalimide;

i, j and k are independently integers from 0-5;

n is an integer from 1 to 4;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (VI)

where

Q is NH, S or O;

Z is CH or N;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₂ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O (CH ₂ ) _k N (CH ₃ ) ₂ , —OC (O) CF ₃ , —OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _k NH ₂ or —O (CH ₂ ) _k N-phthalimide;

i and k are independently integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (VII)

where

Z is CH or N;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

i is an integer from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (VIII)

where

Z is CH or N;

R _{4 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₅ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _t NHCH ₃ , - (CH ₂ ) _t NH ₂ , - (CH ₂ ) _t N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, or —C (O) NH ₂ ;

m is an integer from 1 to 4;

t and q are independently integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the compound of Formula VIII is:

где его таутомер представляет собой:

where its tautomer is:

In one embodiment, the present invention relates to a compound of formula (IX)

where

Z is CH or N;

R _{4 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₅ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _t NHCH ₃ , - (CH ₂ ) _t NH ₂ , - (CH ₂ ) _t N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, or —C (O) NH ₂ ;

m is an integer from 1 to 4;

t and q are independently integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the compound of Formula IX is:

где его таутомер представляет собой:

where its tautomer is:

or

где его таутомер представляет собой:

where its tautomer is:

In one embodiment, the present invention relates to a compound of formula (X)

where

Z is CH or N;

P is CH or N;

R _{4 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₅ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _t NHCH ₃ , - (CH ₂ ) _t NH ₂ , - (CH ₂ ) _t N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, or —C (O) NH ₂ ;

m is an integer from 1 to 4;

t and q are independently integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the compound of Formula X is:

где его таутомер представляет собой:

where its tautomer is:

or

где его таутомер включает:

where its tautomer includes:

In one embodiment, the present invention relates to a compound of formula (XI)

where

Q is S, NH or O;

X is a bond or NH;

A represents substituted or unsubstituted systems of individual, fused or multiple aryl or (hetero) cyclic rings, including saturated and unsaturated N-heterocycles, saturated and unsaturated S-heterocycles and saturated and unsaturated O-heterocycles, saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated mixed heterocycles, aliphatic linear or branched C ₁ -C ₃₀ hydrocarbons;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R is hydrogen, C ₁ -C ₅ linear or branched alkyl; C ₁ -C ₅ linear or branched alkenyl, (CH ₂ ) _l Ph, aryl, (CH ₂ ) _l NHCH ₃ , - (CH ₂ ) _l NH ₂ , - (CH ₂ ) _l N (CH ₃ ) ₂ , C (O) alkyl, C (O) CF ₃ , - (CH ₂ ) _l OMe, - (CH ₂ ) _l OH, or haloalkyl;

R ₃ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, -O (CH ₂ ) _o NHCH ₃ , -O (CH ₂ ) _o NH ₂ , -O (CH ₂ ) _o N (CH ₃ ) ₂ , -O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl , C (O) H or —C (O) NH ₂ ;

i, l and o independently represent integers from 0 to 5;

or its metabolite, isomer, N-oxide, prodrug, hydrate, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (XII)

where

Q is S, NH or O;

X is a bond or NH;

A represents substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl;

wherein optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₃ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, -O (CH ₂ ) _o NHCH ₃ , -O (CH ₂ ) _o NH ₂ , -O (CH ₂ ) _o N (CH ₃ ) ₂ , -O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl , C (O) H or —C (O) NH ₂ ;

i and o independently represent integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer. or combinations thereof.

In one embodiment of Formula XII, R ₃ is different from OMe.

In one embodiment, the present invention relates to a compound of formula (XIII)

where

Q is S, NH or O;

R is hydrogen, C ₁ -C ₅ linear or branched alkyl; C ₁ -C ₅ linear or branched alkenyl, (CH ₂ ) _l Ph, aryl, (CH ₂ ) _l NHCH ₃ , - (CH ₂ ) _l NH ₂ , - (CH ₂ ) _l N (CH ₃ ) ₂ , C (O) alkyl, C (O) CF ₃ , - (CH ₂ ) _l OMe, - (CH ₂ ) _l OH, or haloalkyl;

R ₃ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, -O (CH ₂ ) _o NHCH ₃ , -O (CH ₂ ) _o NH ₂ , -O (CH ₂ ) _o N (CH ₃ ) ₂ , -O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl , C (O) H or —C (O) NH ₂ ;

R _{4 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₅ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _t NHCH ₃ , - (CH ₂ ) _t NH ₂ , - (CH ₂ ) _t N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, or —C (O) NH ₂ ;

m is an integer from 1 to 4;

l, o, t and q are independently integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the compound of Formula XIII is:

или

or

In one embodiment, the present invention relates to a compound of formula (XIV):

where

Q is S, NH or O;

R is hydrogen, C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched alkenyl, (CH ₂ ) _l Ph, aryl, (CH ₂ ) _l NHCH ₃ , - (CH ₂ ) _l NH ₂ , - (CH ₂ ) _l N (CH ₃ ) ₂ , C (O) alkyl, C (O) CF ₃ , - (CH ₂ ) _l OMe, - (CH ₂ ) _l OH or haloalkyl;

R ₃ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, -O (CH ₂ ) _o NHCH ₃ , -O (CH ₂ ) _o NH ₂ , -O (CH ₂ ) _o N (CH ₃ ) ₂ , -O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl , C (O) H or —C (O) NH ₂ ;

R _{4 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

R ₅ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _t NHCH ₃ , - (CH ₂ ) _t NH ₂ , - (CH ₂ ) _t N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino , aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, or —C (O) NH ₂ ;

m is an integer from 1 to 4;

l, o, t and q are independently integers from 0 to 5;

or its metabolite, hydrate, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment, the present invention relates to a compound of formula (XV)

where

Q is S, NH or O;

X is a bond or NH;

R is hydrogen, C ₁ -C ₅ linear or branched alkyl, C ₁ -C ₅ linear or branched alkenyl, (CH ₂ ) _l Ph, aryl, (CH ₂ ) _l NHCH ₃ , - (CH ₂ ) _l NH ₂ , - (CH ₂ ) ₁ N (CH ₃ ) ₂ , C (O) alkyl, C (O) CF ₃ , - (CH ₂ ) _l OMe, - (CH ₂ ) _l OH or haloalkyl;

R ₃ is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, -O (CH ₂ ) _o NHCH ₃ , -O (CH ₂ ) _o NH ₂ , -O (CH ₂ ) _o N (CH ₃ ) ₂ , -O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl , C (O) H or —C (O) NH ₂ ;

R _{4 is} independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, —C (O) NH _2, or a combination thereof;

Rs is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _t NHCH ₃ , - (CH ₂ ) _t NH ₂ , - (CH ₂ ) _t N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, —OCH ₂ Ph, —NHCO-alkyl, COOH, —C (O) Ph, C (O) O-alkyl, C (O) H, or —C (O) NH ₂ ;

m is an integer from 1 to 4;

l, o, t and q are independently integers from 0 to 5;

or its metabolite, hydrate, isomer, N-oxide, prodrug, pharmaceutical product, pharmaceutically acceptable salt, polymorph, tautomer, or a combination thereof.

In one embodiment of Formulas XI, XIII, XIV, and XV, O — R is different from R ₃ .

In one embodiment, the compounds of formula XI-XV contain an R ₃ group at the para position of the benzoyl ring. It was found that the introduction of different functional groups at the para-position of the benzoyl ring likely provides stronger interactions with Cys-241 in the β-tubulin subunit (Figure 5), thereby increasing the activity of inhibiting tubulin polymerization. In addition, modification of the benzoyl ring has helped to understand a possible mechanism of metabolic demethylation. Introduced hydrophobic (OBn 14, OMOM 15) and hydrophilic (OCH ₂ CH ₂ NH ₂ , 18) groups, as shown in figure 3.

Another strategy was proposed based on the hypothesis that, when an alkylating group is introduced at the para-position of the benzoyl ring, it can form an irreversible covalent bond with the Cys-241 mercapto group in the colchicine binding domain and provide irreversible mitotic blocks. The mechanism of inhibition of the assembly of microtubules during the binding of low molecular weight drugs to tubulin through covalent interaction with the amino residue of tubulin is well described. Bai et al. [Bai, R .; Covell, D.G .; Pei, X.F .; Ewell, J. B .; Nguyen, N.Y .; Brossi, A .; Hamel, E., Mapping the binding site of colchicinoids on beta-tubulin. 2-Cmoroacetyl-2-demethylt Mocolchicine covalently reacts predominantly with cysteine 239 and secondarily with cysteine 354. J Biol Chem 2000, 275 (51), 40443-52] reported that 2- and 3-chloroacetyl analogs of dimethylthiocolchicine binding irreversibly to the colchicine site mainly at Cys-241 and prevent colchicine binding agents from binding to the site. Covalent interaction of 2,4-dichlorobenzylthiocyanate (figure 5) with tubulin occurs at several cysteine residues, in particular Cys-241 β-tubulin [Bai, R.L .; Lin, C.M .; Nguyen, N.Y .; Liu, T.Y .; Hamel, E., Identification of the cysteine residue of beta-tubulin alkylated by the antimitotic agent 2,4-dichlorobenzyl thiocyanate, facilitated by separation of the protein subunits of tubulin by hydrophobic column chromatography. Biochemistry 1989,28 (13), 5606-12]. It is believed that the formation of a covalent bond between tubulin and the 2,4-dichlorobenzylmercaptan moiety is reversible. 2-fluoro-1-methoxy-4- (pentafluorophenylsulfonamido) benzene (T138067, figure 5) irreversibly binds β-tubulin through the substitution of the F atom in the para position with the thiol group Cys-241. This compound recruited unmodified tubulin dimers into large amorphous aggregates and thus quickly consumed the tubulin supply available for microtubule formation [Shan, B .; Medina, J. C .; Santha, E .; Frankmoelle, W. P .; Chou, T. C .; Learned, R.M .; Narbut, M. R .; Stott, D .; Wu, P .; Jaen, J. C .; Rosen, T .; Timmermans, P. B .; Beckmann, H., Selective, covalent modification of beta-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors. Proceedings of the National Academy of Sciences of the United States of America 1999, 96 (10), 5686-91].

In one embodiment, a compound of the present invention incorporates an alkylating functional group to form a covalent bond or enhance the interaction between Cys-241 and the benzoyl ring of the compounds of the present invention. Thus, the chloroacetic analogue (12) and trifluoroacetate (13) shown in FIG. 3 were also synthesized and investigated.

In one embodiment, A in formulas I and XI is a substituted or unsubstituted system of separate, fused or multiple aryl or (hetero) cyclic rings, including saturated and unsaturated N-heterocycles, saturated and unsaturated S-heterocycles, and saturated and unsaturated O- heterocycles, saturated or unsaturated cyclic hydrocarbons, saturated or unsaturated mixed heterocycles, aliphatic linear or branched C ₁ -C ₃₀ hydrocarbons.

In one embodiment, group A is substituted or unsubstituted furanyl, benzofuranyl, benzothiophenyl, indolyl, indazolyl, pyridinyl, phenyl, biphenyl, triphenyl, diphenylmethane, adamantanyl, flurenyl, or other heterocyclic analogs such as, for example, pyrrolyl, pyrazolyl, imidazolyl , pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, isoquinolinyl, quinolinyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl, quinalolinyl, phtharynylazinyl, napharynyl , benzodioxolyl, tyranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, tetrahydrothiopyranyl, thiophenyl, thiepinyl, thianaphtenyl, oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxolazyl and isoxadiazolyl.

As used herein, "saturated or unsaturated cyclic hydrocarbons" can be any specified cyclic hydrocarbon, including but not limited to phenyl, biphenyl, triphenyl, naphthyl, cycloalkyl, cycloalkenyl, cyclodienyl, fluorene, adamantane, etc .; "Saturated or unsaturated N-heterocycles" can be any specified N-containing heterocycle, including but not limited to aza- and diazacycloalkyls such as aziridinyl, azetidinyl, diazatidinyl, pyrrolidinyl, piperidinyl, piperazinyl and azocanyl, pyrrolyl, pyrazinyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, pyrrolizinyl, indolyl, indazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, indazolyl, quinolizinyl, cinnolinyl t. "Saturated or unsaturated O-heterocycles" can be any specified O-containing heterocycle, including but not limited to oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, furanyl, pyrylium, benzofuranyl, benzodioxolyl, etc .; "Saturated or unsaturated S-heterocycles" can be any specified S-containing heterocycle, including, but not limited to, tyranyl, thietanyl, tetrahydrothiophenyl, dithiolanyl, tetrahydrothiopyranyl, thiophenyl, thiepinyl, thianaphthenyl, etc .; "Saturated or unsaturated mixed heterocycles" can be any heterocycle containing two or more heteroatoms S, N, or O, including, but not limited to, oxathiolanyl, morpholinyl, thioxanyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and, oxadiazolyl, and oxadiazolyl .d.

In one embodiment, A in formulas II-VII and XII is substituted or unsubstituted phenyl; substituted or unsubstituted indolyl; or substituted or unsubstituted indazolyl. In another embodiment, A in Formula I, II-VII, XI, and XII is substituted or unsubstituted phenyl. In another embodiment, A in Formulas I, II-VII, XI, and XII is substituted or unsubstituted indolyl. In another embodiment, indolyl is substituted or unsubstituted 3-indolyl, 4-indolyl, or 5-indolyl. In another embodiment, group A is substituted or unsubstituted 3-indolyl. In certain embodiments, group A is unsubstituted 3-indolyl. In certain embodiments, group A is unsubstituted 5-indolyl. In certain embodiments, group A is substituted 5-indolyl. In another embodiment, the indolyl is substituted or unsubstituted and is selected from the following structures:

или

or

In another embodiment, A in Formulas I, II-VII, XI, and XII is substituted or unsubstituted indazolyl. In another embodiment, indazolyl is substituted or unsubstituted 3-indazolyl, 4-indazolyl, or 5-indazolyl. In another embodiment, group A is substituted or unsubstituted 3-indazolyl. In certain embodiments, group A is unsubstituted 3-indazolyl. In certain embodiments, group A is unsubstituted 5-indazolyl. In certain embodiments, group A is substituted 5-indazolyl. In another embodiment, the indazolyl is substituted or unsubstituted and is selected from the following structures:

или

or

In one embodiment, the optional substituents at A in formula I, II-VII, XI and XII are absent or include one, two, three, four, or five substituents. In another embodiment, the substituents are the same. In another embodiment, the substituents are different. Individual substituents can be present at the ortho, meta, or para positions. In some embodiments, when two or more substituents are present, one of them is in the para position.

In other embodiments, optional substituents on A include O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, —CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _i NHCH ₃ , - (CH ₂ ) _i NH ₂ , - (CH ₂ ) _i N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH ₂ , NO ₂ or their combination. In another embodiment, A is unsubstituted. In another embodiment, A is substituted with O-alkyl. In another embodiment, A is substituted with O-haloalkyl. In another embodiment, A is substituted with halogen. In another embodiment, A is substituted with NO ₂ . In another embodiment, A is substituted with haloalkyl. In another embodiment, A is substituted with CF ₃ . In another embodiment, A is substituted with CN. In another embodiment, A is substituted with —CH ₂ CN. In another embodiment, A is substituted with NH ₂ . In another embodiment, A is substituted with hydroxyl. In another embodiment, A is substituted with - (CH ₂ ) _i NHCH ₃ . In another embodiment, A is substituted with - (CH ₂ ) _i NH ₂ . In another embodiment, A is substituted with - (CH ₂ ) _i N (CH ₃ ) ₂ . In another embodiment, A is substituted with —OC (O) CF ₃ . In another embodiment, A is substituted with —SO ₂ —aryl. In another embodiment, A is substituted with C ₁ -C ₅ linear or branched alkyl. In another embodiment, A is substituted with haloalkyl. In another embodiment, A is substituted with alkylamino. In another embodiment, A is substituted with aminoalkyl. In another embodiment, A is substituted with —OCH ₂ Ph. In another embodiment, A is substituted with —NHCO-alkyl. In another embodiment, A is substituted with COOH. In another embodiment, A is substituted with —C (O) Ph. In another embodiment, A is substituted with C (O) O-alkyl. In another embodiment, A is substituted with C (O) H. In another embodiment, A is substituted with —C (O) NH ₂ .

In one embodiment, i is an integer from 0 to 5. In another embodiment, i is 0. In another embodiment, i is 1. In another embodiment, i is 2. In another embodiment, i is 3. In another embodiment, implementation i is 4. In another implementation i is 5.

In one embodiment, Z in Formulas I-III and VI-X is CH or N. In another embodiment, Z is CH. In another embodiment, Z is N.

In one embodiment, P in Formula X is CH or N. In another embodiment, P is CH. In another embodiment, P is N.

In one embodiment, Q in formula I, II, VI, XI, XII, and XIII is S, O, or NH. In another embodiment, Q is S. In another embodiment, Q is O. In another embodiment, Q is NH.

In one embodiment, X in Formulas XI and XV is a bond or NH. In another implementation, X is a bond. In another embodiment, X is NH.

In one embodiment, R ₁ in Formula IV is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O- (CH ₂ ) _j N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ or -O (CH ₂ ) _j N-phthalimide. In another embodiment, R ₁ is hydrogen. In another embodiment, R ₁ is O-alkyl. In another embodiment, R ₁ is O-haloalkyl. In another embodiment, R ₁ is halogen. In another embodiment, R ₁ is haloalkyl. In another embodiment, R ₁ is CF ₃ . In another embodiment, R ₁ is CN. In another embodiment, R ₁ is NO ₂ . In another embodiment, R ₁ is —CH ₂ CN. In another embodiment, R ₁ is NH ₂ . In another embodiment, R ₁ is hydroxyl. In another embodiment, R ₁ is COOH. In another embodiment, R ₁ is C (O) H. In another embodiment, R ₁ is NHCO-alkyl. In another embodiment, R ₁ is —O (CH ₂ ) _j OCH ₃ . In another embodiment, R ₁ is —O (CH ₂ ) _j OH. In another embodiment, R ₁ is —O (CH ₂ ) _j NHCH ₃ . In another embodiment, R ₁ is —O (CH ₂ ) _j NH ₂ . In another embodiment, R ₁ is —O- (CH ₂ ) _j N (CH ₃ ) ₂ . In another embodiment, R ₁ is —OC (O) CF ₃ . In another embodiment, R ₁ is —OC (O) CH ₂ Cl. In another embodiment, R ₁ is —OCH ₂ Ph. In another embodiment, R ₁ is —O (CH ₂ ) _j NH ₂ . In another embodiment, R ₁ is —O (CH ₂ ) _j N-phthalimide.

In one embodiment, j is an integer from 0 to 5. In another embodiment, j is 0. In another embodiment, j is 1. In another embodiment, j is 2. In another embodiment, j is 3. In another embodiment, j is 4. In another embodiment, j is 5.

In one embodiment, n is an integer from 1 to 4. In another embodiment, n is 1. In another embodiment, n is 2, in another embodiment, n is 3. In another embodiment, n is 4.

In one embodiment, R ₂ in formula I-VI is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, haloalkyl, CF ₃ , CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO-alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j OH, -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O- (CH ₂ ) _j N (CH ₃ ) ₂ , -OC (O) CF ₃ , -OC (O) CH ₂ Cl, -OCH ₂ Ph, -O (CH ₂ ) _j NH ₂ or -O (CH ₂ ) _j N-phthalimide. In another embodiment, R ₂ is hydrogen. In another embodiment, R ₂ is O-alkyl. In another embodiment, R ₂ is O-haloalkyl. In another embodiment, R ₂ is halogen. In another embodiment, R ₂ is haloalkyl. In another embodiment, R ₂ is CF ₃ . In another embodiment, R ₂ is CN. In another embodiment, R ₂ is NO ₂ . In another embodiment, R ₂ is —CH ₂ CN. In another embodiment, R ₂ is NH ₂ . In another embodiment, R ₂ is hydroxyl. In another embodiment, R ₁ is COOH. In another embodiment, R ₂ is C (O) H. In another embodiment, R ₂ is NHCO-alkyl. In another embodiment, R ₂ is —O (CH ₂ ) _k OCH ₃ . In another embodiment, R ₂ is —O (CH ₂ ) _k OH. In another embodiment, R ₂ is —O (CH ₂ ) _k NHCH ₃ . In another embodiment, R ₂ is —O (CH ₂ ) _k NH ₂ . In another embodiment, R ₂ is —O- (CH ₂ ) _k N (CH ₃ ) ₂ . In another embodiment, R ₂ is —OC (O) CF ₃ . In another embodiment, R ₂ is —OC (O) CH ₂ Cl. In another embodiment, R ₂ is —OCH ₂ Ph. In another embodiment, R ₂ is —O (CH ₂ ) _k NH ₂ . In another embodiment, R ₂ is —O (CH ₂ ) _k N-phthalimide.

In one embodiment, at least one of R ₁ and R ₂ in Formula IV is not hydrogen.

In one embodiment, k is an integer from 0 to 5. In another embodiment, k is 0. In another embodiment, k is 1. In another embodiment, k is 2. In another embodiment, k is 3. In another embodiment k is 4. In another embodiment, k is 5.

In one embodiment, R ₃ in formula XI-XV is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, —CH ₂ CN, NH ₂ , hydroxyl, -O (CH ₂ ) _o NHCH ₃ , -O (CH ₂ ) _o NH ₂ , -O (CH ₂ ) _o N (CH ₃ ) ₂ , -O (CH ₂ ) _o OMe, -O (CH ₂ ) _o OH, -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O ) Ph, C (O) O-alkyl, C (O) H or -C (O) NH ₂ . In another embodiment, R ₃ is hydrogen. In another embodiment, R ₃ is O-alkyl. In another embodiment, R ₃ is O-haloalkyl. In another embodiment, R ₃ is halogen. In another embodiment, R ₃ is NO ₂ . In another embodiment, R ₃ is haloalkyl. In another embodiment, R ₃ is CF ₃ . In another embodiment, R ₃ is CN. In another embodiment, R ₃ is —CH ₂ CN. In another embodiment, R ₃ is NH ₂ . In another embodiment, R ₃ is hydroxyl. In another embodiment, R ₃ is —O (CH ₂ ) _o NHCH ₃ . In another embodiment, R ₃ is —O (CH ₂ ) _o NH ₂ . In another embodiment, R ₃ is —O (CH ₂ ) _o N (CH ₃ ) ₂ . In another embodiment, R ₃ is —O (CH ₂ ) _o OMe. In another embodiment, R ₃ is —O (CH ₂ ) _o OH. In another embodiment, R ₃ is —OC (O) CF ₃ . In another embodiment, R ₃ is —SO ₂ -aryl. In another embodiment, R ₃ is C ₁ -C ₅ linear or branched alkyl. In another embodiment, R ₃ is haloalkyl. In another embodiment, R ₃ is alkylamino. In another embodiment, R ₃ is aminoalkyl. In another embodiment, R ₃ is —OCH ₂ Ph. In another embodiment, R ₃ is —NHCO-alkyl. In another embodiment, R ₃ is COOH. In another embodiment, R ₃ is —C (O) Ph. In another embodiment, R ₃ is C (O) O-alkyl. In another embodiment, R ₃ is C (O) H. In another embodiment, R ₃ is —C (O) NH ₂ .

In one embodiment, o is an integer from 0 to 5. In another embodiment, o is 0. In another embodiment, o is 1. In another embodiment, o is 2. In another embodiment, o is 3. In another embodiment, realization o is 4. In another embodiment, o is 5. In one embodiment, R ₄ in formulas VIII-X and XIII-XV is independently hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN, NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl, C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H, -C (O) NH _2, or a combination thereof. In another embodiment, R ₄ is hydrogen. In another embodiment, R ₄ is O-alkyl. In another embodiment, R ₄ is O-haloalkyl. In another embodiment, R ₄ is halogen. In another embodiment, R ₄ is NO ₂ . In another embodiment, R ₄ is haloalkyl. In another embodiment, R ₄ is CF ₃ . In another embodiment, R ₄ is CN. In another embodiment, R ₄ is —CH ₂ CN. In another embodiment, R ₄ is NH ₂ . In another embodiment, R ₄ is hydroxyl. In another embodiment, R ₄ is - (CH ₂ ) _q NHCH ₃ . In another embodiment, R ₄ is - (CH ₂ ) _q NH ₂ . In another embodiment, R ₄ is - (CH ₂ ) _q N (CH ₃ ) ₂ . In another embodiment, R ₄ is —OC (O) CF ₃ . In another embodiment, R ₄ is —SO ₂ -aryl. In another embodiment, R ₄ is C ₁ -C ₅ linear or branched alkyl. In another embodiment, R ₄ is haloalkyl. In another embodiment, R ₄ is alkylamino. In another embodiment, R ₄ is aminoalkyl. In another embodiment, R ₄ is —OCH ₂ Ph. In another embodiment, R ₄ is —NHCO-alkyl. In another embodiment, R ₄ is COOH. In another embodiment, R ₄ is —C (O) Ph. In another embodiment, R ₄ is C (O) O-alkyl. In another embodiment, R ₄ is C (O) H. In another embodiment, R ₄ is —C (O) NH ₂ .

In one embodiment, q is an integer from 0 to 5. In another embodiment, q is 0. In another embodiment, q is 1. In another embodiment, q is 2. In another embodiment, q is 3. In another embodiment q is 4. In another embodiment, q is 5. In one embodiment, m is an integer from 1 to 4. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4.

In one embodiment, R ₅ in formulas VIII-X and XIII-XV is hydrogen, O-alkyl, O-haloalkyl, F, Cl, Br, I, NO ₂ , haloalkyl, CF ₃ , CN, -CH ₂ CN , NH ₂ , hydroxyl, - (CH ₂ ) _q NHCH ₃ , - (CH ₂ ) _q NH ₂ , - (CH ₂ ) _q N (CH ₃ ) ₂ , -OC (O) CF ₃ , -SO ₂ -aryl , C ₁ -C ₅ linear or branched alkyl, haloalkyl, alkylamino, aminoalkyl, -OCH ₂ Ph, -NHCO-alkyl, COOH, -C (O) Ph, C (O) O-alkyl, C (O) H or -C (O) NH ₂ . In another embodiment, R ₅ is hydrogen. In another embodiment, R ₅ is O-alkyl. In another embodiment, R ₅ is O-haloalkyl. In another embodiment, R ₅ is halogen. In another embodiment, R ₅ is NO ₂ . In another embodiment, R ₅ is haloalkyl. In another embodiment, R ₅ is CF ₃ . In another embodiment, R ₅ is CN. In another embodiment, R ₅ is —CH ₂ CN. In another embodiment, R ₅ is NH ₂ . In another embodiment, R ₅ is hydroxyl. In another embodiment, R ₅ is - (CH ₂ ) _t NHCH ₃ . In another embodiment, R ₅ is - (CH ₂ ) _t NH ₂ . In another embodiment, R ₅ is - (CH ₂ ) _t N (CH ₃ ) ₂ . In another embodiment, R ₅ is —OC (O) CF ₃ . In another embodiment, R ₅ is —SO ₂ -aryl. In another embodiment, R ₅ is C ₁ -C ₅ linear or branched alkyl. In another embodiment, R ₅ is haloalkyl. In another embodiment, R ₅ is alkylamino. In another embodiment, R ₅ is aminoalkyl. In another embodiment, R ₅ is —OCH ₂ Ph. In another embodiment, R ₅ is —NHCO-alkyl. In another embodiment, R ₅ is COOH. In another embodiment, R ₅ is —C (O) Ph. In another embodiment, R ₅ is C (O) O-alkyl. In another embodiment, R ₅ is C (O) H. In another embodiment, R ₅ is —C (O) NH ₂ .

In one embodiment, t is an integer from 0 to 5. In another embodiment, t is 0. In another embodiment, t is 1. In another embodiment, t is 2. In another embodiment, t is 3. In another embodiment, t is 4. In another embodiment, t is 5.

In one embodiment, R in formula XI, XIII-XV is hydrogen, C ₁ -C ₅ linear or branched alkyl; C ₁ -C ₅ linear or branched alkenyl, (CH ₂ ) _l Ph, aryl, (CH ₂ ) _l NHCH ₃ , - (CH ₂ ) _l NH ₂ , - (CH ₂ ) _l N (CH ₃ ) ₂ , C (O) alkyl, C (O) CF ₃ , - (CH ₂ ) _l OMe, - (CH ₂ ) _l OH, or haloalkyl. In another embodiment, R is hydrogen. In another embodiment, R is C ₁ -C ₅ linear or branched alkyl. In another embodiment, R is C ₁ -C ₅ linear or branched alkenyl. In another embodiment, R is (CH ₂ ) _l Phe. In another embodiment, R is aryl. In another embodiment, R is (CH ₂ ) _l NHCH ₃ . In another embodiment, R is - (CH ₂ ) _l NH ₂ . In another embodiment, R is - (CH ₂ ) _l N (CH ₃ ) ₂ . In another embodiment, R is C (O) alkyl. In another embodiment, R is C (O) CF ₃ . In another embodiment, R is - (CH ₂ ) _l OMe. In another embodiment, R is - (CH ₂ ) _l OH. In another embodiment, R is haloalkyl.

In one embodiment, l is an integer from 0 to 5. In another embodiment, l is 0. In another embodiment, l is 1. In another embodiment, l is 2. In another embodiment, l is 3. In another embodiment, l is 4. In another embodiment, l is 5.

As used herein, the term "alkyl" can be any linear or branched alkyl group containing up to 30 carbon atoms, unless otherwise specified. In another embodiment, alkyl is C ₁ -C ₅ alkyl. In another embodiment, alkyl is C ₂ -C ₅ alkyl. In another embodiment, alkyl is C ₁ -C ₇ alkyl. The alkyl group may be a single substituent or may be a component of a larger substituent such as alkoxy, haloalkyl, arylalkyl, alkylamino, dialkylamino, alkylamide o, alkylurea, etc. Preferred alkyl groups are methyl, ethyl and propyl, and thus halomethyl, dihalomethyl, trihalomethyl, haloethyl, dihaloethyl, trihaloethyl, halopropyl, dihalopropyl, trihalopropyl, methoxy, ethoxy, propoxy, arylmethyl, arylamino, ethylamino, dimethylamino, diethylamino, methylamido, acetamido, propylamido, halomethylamido, haloethylamido, halopropylamido, methylurea, ethylurea, propylurea, etc.

As used herein, the term "aryl" refers to any aromatic ring substituent that is directly bonded to the ring member (s) of R ¹ or R ² . The aryl group can be a single substituent, or the aryl group can be a component of a larger substituent such as arylalkyl, arylamino, arylamido, etc. Typical aryl groups include, but are not limited to, phenyl, toluyl, xylyl, furanyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiophenyl, pyrrolylamino, phenylmethyl, phenylamino, phenylamido, phenylmethyl. etc.

As used herein, the term "aminoalkyl" refers to an amino group substituted with an alkyl group as defined above. Aminoalkyl refers to monoalkylamine, dialkylamine, or trialkylamine. Non-limiting examples of aminoalkyl groups are —N (Me) ₂ , —NHMe, —NH ₃ .

A “haloalkyl” group refers, in another embodiment, to an alkyl group as defined above substituted with one or more halogen atoms, for example F, Cl, Br, or I. Non-limiting examples of haloalkyl groups are CF ₃ , CF ₂ CF ₃ , CH ₂ CF ₃ .

In one embodiment, the invention provides a compound of the present invention, or a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, isomer, N-oxide, prodrug, tautomer, polymorph, or combinations thereof. In one embodiment, the present invention provides a metabolite of a compound of the present invention. In another embodiment, the present invention provides a pharmaceutically acceptable salt of a compound of the present invention. In another embodiment, the present invention provides a pharmaceutical product of a compound of the present invention. In another embodiment, the present invention provides a hydrate of a compound of the present invention. In another embodiment, the present invention provides an isomer of a compound of the present invention. In another embodiment, the present invention provides an N-oxide of a compound of the present invention. In another embodiment, the present invention provides a prodrug of a compound of the present invention. In another embodiment, the present invention provides a tautomer of a compound of the present invention. In another embodiment, the present invention provides a polymorph of a compound of the present invention. In another embodiment, the present invention provides a composition comprising a compound of the present invention, as described herein, or, in another embodiment, a combination of a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, isomer, N-oxide, prodrug, or polymorph of the compound according to the present invention.

The compounds of the present invention can also exist in the form of a hydrate, which means that the compound further comprises a stoichiometric or non-stoichiometric amount of water attached via non-covalent intermolecular bonds.

The compounds of the present invention can exist as one or more possible tautomers, and depending on the specific conditions, some or all of the tautomers can be separated into separate and different molecules. It should be understood that all possible tautomers, including all additional enol and keto tautomers, and / or isomers are encompassed by the present invention. For example, the invention includes, but is not limited to, the following tautomers.

Tautomerization of the imidazole ring

Indazole ring tautomers

Tautomers of the benzimidazole ring

Tautomers of the pyridinoimidazole ring

The tautomers of the present invention are tautomers that are freely convertible into one another, but are not inseparable mixtures. Imidazoles, thiazole and other ring systems of the present invention can exist as tautomers. All tautomers are considered part of the invention.

The invention includes “pharmaceutically acceptable salts” of the compounds of the present invention, which can be prepared by reacting a compound of the present invention with an acid or base. Certain compounds, in particular those containing acidic or basic groups, can also be in the form of a salt, preferably a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the free bases or free acids are not biologically or otherwise undesirable. Salts are prepared using inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., organic acids such as acetic acid, propanoic acid, glycolic acid, grape acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, n-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. Other salts are known to those skilled in the art and can be readily adapted for use in accordance with the present invention.

Suitable pharmaceutically acceptable amine salts of the compounds of the present invention can be prepared from an inorganic acid or an organic acid. In one embodiment, examples of inorganic amine salts are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2-hydroxyethyl sulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphates, sulfates, sulfates sulfonic acids (alkyl sulfonates, arylsulfonates, halogenated alkyl sulfonates, halogenated arylsulfonates), sulfonates and thiocyanates.

In one embodiment, examples of organic amine salts can be selected from the classes of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfoorganic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphors, camphorsulfonates, cyclohexylsulfamates, cyclopentane propionates, calcium edetates, camsylates, carbonates, clavamatiulanates, digonylconchylate ethanesulfonates, edetates, edisilates, estolates, esilates, fumarates, formates, fluorides, galacturonates, gluconates, glutamates, glycolate, glucorates, glucoheptanoates, glycerophosphates, gluceptates, hydroxylarsanilates, glutatexanes, salts ilresorcinates, hydroxybenzoates, hydroxynaphthoates, hydrofluorates, lactates, lactobionates, laurates, malates, maleates, methylenebis (beta-oxynaphthoates), malonates, mandelates, mesylates, methanesulfonates, methyl bromides, methyl nitrates, methylsulfonates, monocalonates, maleucalinates naphthalenesulfonates, nicotinates, nitrates, napsilates, N-methylglucamine, oxalates, octanoates, oleates, pamoates, phenylacetates, picrates, phenylbenzoates, pivalates, propionates, phthalates, phenylacetate, pectinates, phenylpropionates, palmitates, pentinates, polypropionates, palmitates, polyrupionates, palmitates succinates, stearates, sulfonylate, subacetates, tartrates, theophylline acetates, p-toluenesulfonates (tosylates), trifluoroacetates, terephthalates, tannates, theoclates, trihaloacetates, triethiodide, tricarboxylates, undecanoates and valerates.

In one embodiment, examples of inorganic salts of carboxylic acids or hydroxyls can be selected from ammonium salts, alkali metals, including lithium, sodium, potassium, cesium; alkaline earth metals including calcium, magnesium, aluminum; zinc, barium, choline, quaternary ammonium.

In another embodiment, examples of organic carboxylic acid or hydroxyl salts can be selected from arginine salts, organic amines including aliphatic organic amines, alicyclic organic amines, aromatic organic amines, benzathines, tert-butylamines, benetamines (N-benzylphenethylamine), dicyclohexylamines, dicyclohexylamines, dicyclic organic amines , diethanolamines, ethanolamines, ethylenediamines, hydrabamines, imidazoles, lysines, methylamines, megamines, N-methyl-D-glucamines, N, N'-dibenzylethylenediamines, nicotinamides, organic amines, ornithines, pyridines, picolines, piperazines, trisines ) methylamines, triethylamines, triethanolamines, trimethylamines, trometamines and ureas.

In one embodiment, the term "isomer" includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and so on.

In one embodiment, the compounds of the present invention are pure (E) isomers. In another embodiment, the compounds of the present invention are pure (Z) isomers. In another embodiment, the compounds of the present invention are a mixture of the (E) and (Z) isomers. In one embodiment, the compounds of the present invention are pure (R) isomers. In another embodiment, the compounds of the present invention are pure (S) -isomers. In another embodiment, the compounds of the present invention are a mixture of the (R) - and (S) -isomers.

The compounds of the present invention can also be present as a racemic mixture containing substantially equivalent amounts of stereoisomers. In another embodiment, the compounds of the present invention can be prepared or otherwise isolated using known methods that provide one stereoisomer substantially free of the corresponding other stereoisomer (i.e., substantially pure). By substantially pure is meant a stereoisomer that has a purity of at least 95%, more preferably at least about 98%, most preferably at least about 99%.

In one embodiment, salts can be prepared using conventional methods such as reacting the free base or free acid product with one or more equivalents of the corresponding acid or base in a solvent or medium in which the salt is insoluble, or in a solvent such as water , which is removed under vacuum or by lyophilization, or by exchanging the ions of the existing salt for another ion, or using a suitable ion exchange resin.

In one embodiment, the invention provides a compound of the present invention or an N-oxide thereof.

The compounds of the present invention can also be administered as metabolites. In one embodiment, the term "metabolite" refers to any substance obtained from another substance by metabolism or metabolic process. In another embodiment, metabolites of the present invention comprise M1-M14, such as described in Example 6 and Figures 8-11.

Thus, certain derivatives, which as such have little or no pharmacological activity, when administered orally or on the surface of the body, can be converted into compounds of the present invention having the desired activity, for example, by hydrolytic cleavage. Additional information on the use of prodrugs can be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (Higuchi and Stella); and Bioreversible Carriers in Drug Design, Pergamon Press (ed. E in Roche, American Pharmaceutical Association) (1987), the contents of each of which are incorporated by reference in their entirety.

Prodrugs can be prepared, for example, by replacing the corresponding functional groups contained in the compounds of the present invention with certain moieties known to those skilled in the art as pro moieties. Examples of such prodrugs include, but are not limited to, prodrugs wherein a hydrogen atom in the alcohol functional group (—OH) is replaced with a C ₁ -C ₆ alkyl to form an ether; and (ii) the hydrogen atom in the secondary amino group is replaced by a C ₁ -C ₁₀ alkanoyl to form an amide.

Pharmaceutical composition

Another aspect of the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to some aspects of the present invention. The pharmaceutical composition may contain one or more of the above compounds according to the present invention. Typically, the pharmaceutical composition of the present invention contains a compound of the present invention, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" refers to any suitable adjuvants, carriers, excipients or stabilizers, and can be in solid or liquid form such as tablets, capsules, powders, solutions, suspensions or emulsions.

Typically, the composition contains from about 0.01 to 99 percent, preferably from about 20 to 75 percent of the active compound (s), together with adjuvants, carriers and / or excipients. While the needs of individuals may vary, determining the optimal ranges for effective amounts of each component can be within the skill of the art. Typical dosages contain from about 0.01 to about 100 mg / kg body weight. Preferred dosages contain from about 0.1 to about 100 mg / kg body weight. Most preferred dosages contain from about 1 to about 100 mg / kg body weight. Specialists in the art can also easily determine the treatment regimen with the introduction of the compounds according to the present invention. That is, the frequency of administration and the size of the dose can be set using conventional determination of the optimal characteristics, preferably to minimize any side effects.

Solid dosage forms can be of the conventional type. The solid form may be a capsule, etc., such as a conventional gelatin-type capsule containing the compounds of the present invention and a carrier, for example, lubricants and excipients such as lactose, sucrose and corn starch. In another embodiment, said compounds are formulated as tablets using a conventional tablet base such as lactose, sucrose or corn starch, in combination with binders such as gum arabic, corn starch or gelatin, disintegrants such as corn starch, potato starch or alginic acid, or a lubricant such as stearic acid or magnesium stearate.

Tablets, capsules, etc. may also contain a binder such as gum tragacanth, gum arabic, corn starch or gelatin; excipients such as dicalcium phosphate; a leavening agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetener such as sucrose, lactose, or saccharin. If the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials can be incorporated as coatings or to modify the physical form of the dosage form. For example, tablets can be coated with shellac, sugar, or both. The syrup may contain, in addition to the active ingredient, sucrose as a sweetener, methyl and propyl parabens as preservatives, a color and a flavoring agent such as cherry or orange flavor.

In the case of oral therapeutic administration, these active compounds can be co-administered with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, etc. These compositions and preparations may contain at least 0.1% active compound. The percentages of the compound in these compositions can of course vary, and traditionally ranges from about 2% to about 60% of the form by weight. The amount of active compound in these therapeutically suitable compositions is such as to provide a suitable dosage. Preferred compositions according to the present invention are prepared such that the oral dosage form contains from about 1 mg to 800 mg of active compound.

The active compounds of the present invention can be administered orally, for example, together with an inert diluent or an assimilable edible carrier, or they can be enclosed in hard or soft shell capsules, or compressed into tablets, or incorporated directly into food.

Pharmaceutical forms suitable for administration by injection include sterile aqueous solutions or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and have sufficient fluidity for ease of use in a syringe. It must be stable under the conditions of receipt and storage and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (eg, glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

The compounds or pharmaceutical compositions of the present invention can also be administered as injectable dosages of a solution or suspension of said materials in a physiologically acceptable diluent together with a pharmaceutical adjuvant, carrier or excipient. These adjuvants, carriers and / or excipients include, but are not limited to, sterile liquids such as water and oils, with or without added surfactants and other pharmaceutically and physiologically acceptable components. Illustrative oils are oils of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, preferred liquid carriers for injectable solutions are water, saline, aqueous dextrose, and a solution of similar sugars and glycols such as propylene glycol or polyethylene glycol.

These active compounds can also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water mixed with a suitable surfactant such as hydroxypropyl cellulose. You can also get dispersions in glycerin, liquid polyethylene glycols and mixtures thereof in oils. Illustrative oils are oils of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, or mineral oil. In general, the preferred liquid carriers, especially for injectable solutions, are water, saline, aqueous dextrose, and a solution of similar sugars and glycols such as propylene glycol or polyethylene glycol. These preparations contain a preservative under standard conditions of storage and use to prevent the growth of microorganisms.

For aerosol use, the compounds of the present invention as a solution or suspension may be packaged in containers containing an injected aerosol in conjunction with suitable propellants, for example, hydrocarbon propellants such as propane, butane, or isobutane, and conventional adjuvants. The materials of the present invention can also be administered in atmospheric pressure forms such as a nebulizer or nebulizer.

In one embodiment, the compounds of the present invention are administered in combination with an anti-cancer agent. In one embodiment, the anti-cancer agent is a monoclonal antibody. In some embodiments, the monoclonal antibodies are used to diagnose, monitor, or treat cancer. In one embodiment, the monoclonal antibodies target specific antigens in cancer cells. In one embodiment, the monoclonal antibody acts as a cancer cell receptor antagonist. In one embodiment, the monoclonal antibodies enhance the patient's immune response. In one embodiment, the monoclonal antibodies target cell growth factors and thereby block the growth of cancer cells. In one embodiment, the anti-cancer monoclonal antibodies are conjugated or linked to anti-cancer drugs, radioisotopes, other biological response modifiers, other toxins, or a combination thereof. In one embodiment, the anti-cancer monoclonal antibodies are conjugated or linked to a compound of the present invention, such as described herein above.

Another aspect of the present invention relates to a method for treating cancer, comprising selecting a subject in need of cancer treatment and administering to the subject a pharmaceutical composition comprising a compound according to the first aspect of the present invention and a pharmaceutically acceptable carrier under conditions that are effective for treating cancer.

Administration of the compounds of the present invention can be carried out systemically or alternatively directly to a specific site where cancer cells or precancerous cells are present. Thus, administration can be carried out by any method that is effective for delivering the compounds or pharmaceutical compositions to cancer cells or precancerous cells. Typical routes of administration include, without limitation, administration of the compounds or compositions by oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavitary or intravesical, intraocular, intraarterial, intralesional, or membrane applications, such as those found in the nose, throat, and bronchial tubes.

Biological activity

The compounds of the present invention are suitable for the treatment or prevention of various forms of cancer, in particular prostate cancer, breast cancer, drug resistant breast cancer, ovarian cancer, skin cancer (e.g. melanoma), drug resistant melanoma, lung cancer, colon cancer, leukemia, kidney cancer, CNS cancer (eg, glioma, glioblastoma). Methods for the treatment of these various types of cancer are substantiated in the examples given in the present description. In addition, given the mode of action as tubulin inhibitors, other cancers are likely to be treatable or preventable when the compounds or compositions of the present invention are administered to a patient. Preferred compounds of the present invention selectively destroy cancer cells, deplete cancer cells, but preferably non-normal cells. It is important to note that harm to normal cells is minimized since cancer cells are susceptible to destruction when using significantly lower concentrations of the compounds of the present invention.

Thus, a further aspect of the present invention relates to a method of destroying a cancer cell, comprising: providing a compound of the present invention and then contacting the cancer cell with the compound under conditions that are effective to destroy the contacted cancer cell. In various embodiments of the destruction of cancer cells, the cells to be destroyed can be in vivo or ex vivo (i.e., in culture).

An additional aspect of the present invention relates to a method for treating or preventing a cancerous condition, comprising: providing a compound of the present invention and then administering an effective amount of the compound to a patient using a method that is effective to cure or prevent a cancerous condition.

In one embodiment, the patient being treated has a precancerous condition, and administration of the compound is effective to prevent the precancerous condition from progressing to a cancerous condition. This prevention can occur by destroying the precancerous cell before its additional development to a cancerous state or simultaneously with it.

In another embodiment, the patient being treated is characterized by a cancerous state, and administration of the compound is effective to regress the cancerous state or suppress the development of a cancerous state, i. E. stopping its development or reducing the rate of development, which preferably occurs when cancer cells are destroyed regardless of their location in the patient's body, that is, cancer cells that are located in the primary site of the tumor, or cancer cells that have formed metastases and created secondary tumors in the patient's body.

If the compounds or pharmaceutical compositions of the present invention are administered to treat or prevent a cancerous condition, the pharmaceutical composition may also contain other therapeutic agents, or it may be used in conjunction with other treatment regimens currently known or to be developed subsequently to treat different types of cancer. Examples of other therapeutic agents or treatment regimens include, but are not limited to, radiation therapy, immunotherapy, chemotherapy, surgery, and combinations thereof.

In one embodiment, the invention provides compounds and compositions, including any of the embodiments described herein, for use in any of the methods of the present invention. In one embodiment, a compound of the present invention, or a composition containing it, can be used to suppress, attenuate, enhance, or stimulate a targeted response in a subject, as would be appreciated by those skilled in the art. In another embodiment, the compositions may contain additional active ingredients that have a suitable activity for the particular application for which the compound of the present invention is administered.

In one embodiment, the present invention provides a method of treating, ameliorating, reducing the severity, reducing the risk of developing or suppressing cancer, comprising administering a compound of the present invention to a subject suffering from cancer under conditions that are effective for treating cancer.

Drug resistance is a major reason for the failure of cancer chemotherapy. One of the main factors of multidrug resistance is the increased expression of P-glycoprotein (P-gp). The specified protein is a clinically important transport protein belonging to the family of ATP-binding cassette transporters of the cell membrane. It can remove substrates, including anti-cancer drugs, from tumor cells through an ATP-dependent mechanism.

In one embodiment, the present invention provides methods of: a) treating, ameliorating, reducing the severity, reducing the risk, or suppressing cancer; b) treating, weakening, reducing the severity, reducing the risk, or suppressing prostate cancer; c) treating, weakening, reducing the severity, reducing the risk, or suppressing drug-resistant prostate cancer; d) treating, alleviating, reducing the severity, reducing the risk, or suppressing breast cancer; e) treating, attenuating, reducing the severity, reducing the risk, or suppressing drug-resistant breast cancer; f) treating, alleviating, reducing the severity, reducing the risk, or suppressing ovarian cancer; g) treating, attenuating, reducing the severity, reducing the risk, or suppressing drug-resistant ovarian cancer; h) treating, alleviating, reducing the severity, reducing the risk, or suppressing skin cancer; i) treating, alleviating, reducing the severity, reducing the risk, or suppressing melanoma; j) treating, ameliorating, reducing the severity, reducing the risk, or suppressing metastatic melanoma; k) treating, ameliorating, reducing the severity, reducing the risk, or suppressing drug-resistant melanoma; l) treating, attenuating, reducing the severity, reducing the risk, or suppressing lung cancer; m) treating, weakening, reducing the severity, reducing the risk, or suppressing colon cancer; n) treating, alleviating, reducing the severity, reducing the risk, or suppressing glioma; o) treating, weakening, reducing the severity, reducing the risk, or suppressing leukemia; p) treating, alleviating, reducing the severity, reducing the risk, or suppressing lymphoma; q) treating, attenuating, reducing the severity, reducing the risk, or suppressing kidney cancer; r) treating, weakening, reducing the severity, reducing the risk, or suppressing CNS cancer; s) treating, weakening, reducing the severity, reducing the risk, or suppressing uterine cancer; t) treating, attenuating, reducing the severity, reducing the risk, or suppressing drug-resistant uterine cancer; u) treating drug-resistant tumor or tumors, wherein said tumor is selected from the group consisting of prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, glial tumor, ovarian cancer, cancer drug-resistant ovary, skin cancer, melanoma, drug-resistant melanoma, lung cancer, colon cancer, leukemia, lymphoma, kidney cancer, CNS cancer, uterine cancer, uterine cancer with drug stability and their combinations; comprising the administration of a compound according to the present invention and / or a metabolite, a pharmaceutically acceptable salt, a pharmaceutical product, a tautomer. a hydrate, isomer, N-oxide, prodrug, polymorph of the specified compound, or any combination thereof. In another embodiment, the subject has previously received treatment with chemotherapy, radiotherapy, or biological therapy.

The compounds of the present invention are useful for treating, reducing the severity, reducing the risk, or suppressing cancer, metastatic cancer, drug resistant tumors, drug resistant cancers, and various forms of cancer. In a preferred embodiment, the cancer is prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, uterine cancer, drug-resistant uterine cancer, skin cancer (e.g., melanoma) , drug-resistant melanoma, lung cancer, colon cancer, leukemia, lymphoma, head and neck cancer, pancreas, esophagus, kidney cancer, or CNS cancer (eg, glioma, glioblastoma). Methods for the treatment of these various types of cancer are substantiated in the examples given in the present description. In addition, given the mode of action as tubulin inhibitors, other cancers are likely to be treatable or preventable when the compounds or compositions of the present invention are administered to a patient. Preferred compounds of the present invention selectively destroy cancer cells, deplete cancer cells, but preferably non-normal cells. It is important to note that harm to normal cells is minimized since cancer cells are susceptible to destruction when using significantly lower concentrations of the compounds of the present invention.

In some embodiments, the present invention provides the use of a compound described herein, or a metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, polymorph, hydrate, isomer, N-oxide, prodrug, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, or suppression of cancer in a subject. In another embodiment, the cancer is adrenal cortex carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, drug-resistant breast cancer, glioma, cerebellar astrocytoma, cerebellar astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors of the pineal gland, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's tumor family (Pnet), extracranial embryonic cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, stomach cancer, embryonic cell tumor, extragonadal gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic leukemia, oral cancer , liver cancer, lung cancer, non-small cell lung cancer, m aecellular lymphoma, AIDS-related lymphoma, (primary) central nervous system lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant mesothelioma, melanoma, drug-resistant melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma, multiple myeloma , neoplasms of plasma cells, fungal mycosis, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelium cancer, embryonic ovarian cell tumor, borderline ovarian tumor, drug-resistant ovarian cancer, pancreatic cancer , exocrine pancreatic cancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, prostate cancer, drug-resistant prostate cancer, rhabdomyosarcoma, direct cancer colon, kidney cancer, renal cell carcinoma, salivary gland cancer, Sesari's syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaloshi's sarcoma, skin cancer, melanoma, drug-resistant melanoma, small intestine cancer, soft tissue sarcoma, testicular cancer, malignant thymoma, thyroid cancer, urethra cancer, uterine cancer, drug-resistant uterine cancer, sarcoma, rare cancers in children, vaginal cancer, vulvar cancer, Wilms tumor, or any combination thereof. In another embodiment, the subject has previously received treatment with chemotherapy, radiotherapy, or biological therapy.

In some embodiments, the present invention provides the use of a compound described herein, or a metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, polymorph, hydrate, isomer, N-oxide, prodrug, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, or suppression of metastatic cancer in a subject. In another embodiment, the cancer is adrenal cortex carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, drug-resistant breast cancer, glioma, cerebellar astrocytoma, cerebellar astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors of the pineal gland, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's tumor family (Pnet), extracranial embryonic cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, stomach cancer, embryonic cell tumor, extragonadal gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic leukemia, oral cancer , liver cancer, lung cancer, non-small cell lung cancer, m aecellular lymphoma, AIDS-related lymphoma, (primary) central nervous system lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant mesothelioma, melanoma, drug-resistant melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma, multiple myeloma , neoplasms of plasma cells, fungal mycosis, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelium cancer, embryonic ovarian cell tumor, borderline ovarian tumor, drug-resistant ovarian cancer, pancreatic cancer , exocrine pancreatic cancer, islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, prostate cancer, drug-resistant prostate cancer, rhabdomyosarcoma, direct cancer colon, kidney cancer, renal cell carcinoma, salivary gland cancer, Sesari's syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaloshi's sarcoma, skin cancer, melanoma, drug-resistant melanoma, small intestine cancer, soft tissue sarcoma, testicular cancer, malignant thymoma, thyroid cancer, urethra cancer, uterine cancer, drug-resistant uterine cancer, sarcoma, rare cancers in children, vaginal cancer, vulvar cancer, Wilms tumor, or any combination thereof.

In some embodiments, the present invention provides the use of a compound described herein, or a metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, polymorph, hydrate, isomer, N-oxide, prodrug, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, or suppression of drug-resistant or resistant cancer in a subject. In another embodiment, the cancer is adrenal cortex carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, drug-resistant breast cancer, glioma, cerebellar astrocytoma, cerebellar astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors of the pineal gland, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's tumor family (Pnet), extracranial embryonic cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, stomach cancer, embryonic cell tumor, extragonadal gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic leukemia, oral cancer , liver cancer, lung cancer, non-small cell lung cancer, m aecellular lymphoma, AIDS-related lymphoma, (primary) central nervous system lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant mesothelioma, melanoma, drug-resistant melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma, multiple myeloma , neoplasms of plasma cells, fungal mycosis, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelium cancer, embryonic ovarian cell tumor, borderline ovarian tumor, pancreatic cancer, exocrine gland islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, prostate cancer, rhabdomyosarcoma, rectal cancer, kidney cancer, renal cell carcinoma, salivary gland cancer, Sesari syndrome, skin cancer, to cutaneous T-cell lymphoma, skin cancer, Kaloshi's sarcoma, skin cancer, melanoma, drug-resistant melanoma, small intestine cancer, soft tissue sarcoma, testicular cancer, malignant thymoma, thyroid cancer, urethra cancer, uterine cancer, sarcoma, rare cancers in children, vaginal cancer, vulvar cancer, Wilms tumor, or any combination thereof.

In one embodiment, the term "metastatic cancer" refers to cancer that has spread (metastasized) from the original site to another area of the body. In theory, all cancers have the potential to spread. The possibility of developing metastases depends on a complex interaction of many factors that affect cancer cells, including the type of cancer, the degree of maturity (differentiation) of tumor cells, the location and duration of the cancer, as well as other factors not fully understood. Metastases spread in three ways - by local expansion of the tumor into surrounding tissues, through the bloodstream to distant sites, or through the lymphatic system to nearby or distant lymph nodes. Each type of cancer can have a typical spread. The name of the tumor is determined by the primary site (for example, breast cancer that has spread to the brain is called breast cancer that has spread to the brain).

In one embodiment, the term "drug resistant cancer" refers to cancer cells that become resistant to chemotherapy. Cancer cells can acquire resistance to chemotherapy through a variety of mechanisms, including mutation or overexpression of the target drug, inactivation of the drug, or removal of the drug from the cell. Tumors that recur after the initial response to chemotherapy may be multidrug resistant (multidrug resistant). In the traditional case of drug resistance, one or more cells from the tumor population acquire genetic changes that confer drug resistance. Accordingly, the causes of drug resistance are, among others: a) mutation (change) of some cells not destroyed by chemotherapy, leading to drug resistance. As a result, the number of resistant cells increases and may begin to exceed the number of cells susceptible to chemotherapy; b) gene amplification. A cancer cell can make hundreds of copies of a particular gene. This gene triggers an increased production of a protein, which makes the use of an anticancer drug ineffective; c) removing the drug from cancer cells as soon as it enters the cell by a molecule called P-glycoprotein; d) stopping the flow of the drug into cancer cells due to the cessation of the functioning of the protein that ensures the transport of the drug through the cell wall; f) recognition by cancer cells of a way to repair DNA breaks caused by certain anti-cancer drugs; f) development of a drug inactivation mechanism in cancer cells. One of the main factors of multidrug resistance is the increased expression of P-glycoprotein (P-gp). The specified protein is a clinically important transport protein belonging to the family of ATP-binding cassette transporters of the cell membrane. It can remove substrates, including anti-cancer drugs, from tumor cells through an ATP-dependent mechanism. Thus, resistance to anticancer agents used in chemotherapy is the main reason for ineffective treatment of malignant disorders, causing an increase in tumor resistance. Drug resistance is the main reason for the ineffectiveness of cancer chemotherapy.

In one embodiment, the term "resistant cancer" refers to a drug resistant cancer such as described above in this application. In another embodiment, "resistant cancer" refers to cancer cells that become resistant to any method of treatment, such as chemotherapy, radiotherapy, or biological therapy.

In one embodiment, the present invention relates to a method of treating, ameliorating, reducing the severity, reducing the risk, or suppressing cancer in a subject, where the subject has previously received treatment with chemotherapy, radiotherapy, or biological therapy.

In one embodiment, the term "chemotherapy" refers to a chemical method for treating cancer, such as the use of drugs that directly kill cancer cells. These drugs are called "anticancer" drugs or "antineoplastic drugs". More than 100 drugs are currently used in cancer therapy. When treating a specific type of cancer, chemotherapy is used to control tumor growth if a cure is not possible; to shrink a tumor before undergoing surgery or radiation therapy; to relieve symptoms (such as pain); and to kill microscopic cancer cells that may persist after a known tumor has been removed by surgery (called adjuvant therapy). Adjuvant therapy is given to prevent the possible recurrence of cancer.

In one embodiment, the term "radiotherapy" refers to the use of high energy X-rays and similar beams (such as electrons) to treat a disease. Many people with cancer receive radiation therapy as part of their treatment. Radiotherapy can be performed as external radiotherapy using X-rays from a source outside the body, or as internal radiotherapy if the source of the rays is inside the body. The action of radiotherapy is based on the destruction of cancer cells in the affected area. Although normal cells can also be destroyed with radiotherapy, they can usually repair themselves. Radiation therapy can cure some cancers and also reduce the chance of cancer coming back after surgery. It can be used to reduce cancer symptoms.

In one embodiment, the term "biological therapy" refers to the use of substances that are usually found in the body to destroy cancer cells. There are several types of treatments, including: monoclonal antibodies, cancer cell growth inhibitors, vaccines, and gene therapy. Biological therapy is also called immunotherapy.

In one embodiment, the present invention provides a method of treating a subject suffering from prostate cancer, metastatic prostate cancer, refractory prostate cancer or drug-resistant prostate cancer, comprising the step of administering to said subject a compound of the present invention or a metabolite thereof, a pharmaceutically acceptable salt, a pharmaceutical a product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof or a composition containing it in an amount that is effective for treating prostate cancer in a subject. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In one embodiment, the present invention provides a method for attenuating, reducing the severity, reducing the risk, delaying the progression or suppression of prostate cancer, metastatic prostate cancer, refractory prostate cancer or drug-resistant prostate cancer in a subject, comprising administering to the subject a compound of the present invention and / or its metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof or a composition containing it. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In one embodiment, the present invention provides a method of treating a subject suffering from breast cancer, metastatic breast cancer, drug-resistant breast cancer or drug-resistant breast cancer, comprising the step of administering to said subject a compound of the present invention or a metabolite thereof, a pharmaceutically acceptable salt, a pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof or a composition containing it. In another implementation, the subject is a male or female. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In one embodiment, the present invention provides a method of attenuating, reducing the severity, reducing the risk, delaying the progression or suppression of breast cancer, metastatic breast cancer, refractory breast cancer or drug-resistant breast cancer in a subject, comprising the step of administering to said subject a compound of the present invention or its metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof or a composition containing it. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, delay of progression or suppression of ovarian cancer, metastatic ovarian cancer, refractory ovarian cancer, or drug-resistant ovarian cancer in a subject. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In one embodiment, the present invention provides a method of treating, ameliorating, reducing the severity, reducing the risk, or suppressing melanoma, metastatic melanoma, refractory melanoma, or drug-resistant melanoma in a subject, comprising administering to the subject a compound of the present invention and / or a metabolite thereof, pharmaceutically an acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, delayed progression or suppression of lung cancer, metastatic lung cancer, resistant lung cancer, or drug-resistant lung cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, delayed progression or suppression of non-small cell lung cancer, metastatic small cell lung cancer, resistant small cell lung cancer, or drug-resistant small cell lung cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, delay of progression or suppression of colon cancer, metastatic colon cancer, resistant colon cancer, or drug-resistant colon cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, risk reduction, delay in progression or suppression of leukemia, metastatic leukemia, resistant leukemia, or drug-resistant leukemia. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, risk reduction, delay in progression or suppression of glioma, metastatic glioma, resistant glioma, or drug-resistant glioma. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, risk reduction, delay in progression or suppression of lymphoma, metastatic lymphoma, resistant lymphoma, or drug-resistant lymphoma. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, risk reduction, delaying progression or suppression of head and neck cancer, metastatic head and neck cancer, resistant head and neck cancer, or drug-resistant head and neck cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, delayed progression or suppression of pancreatic cancer, metastatic pancreatic cancer, resistant pancreatic cancer, or drug-resistant pancreatic cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, reduce the risk, delay the progression or suppression of esophageal cancer, metastatic esophageal cancer, resistant esophageal cancer, or drug-resistant esophageal cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, risk reduction, delaying progression or suppression of kidney cancer, metastatic kidney cancer, resistant kidney cancer, or drug-resistant kidney cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the present invention provides the use of a compound described herein, or a metabolite thereof, a pharmaceutically acceptable salt, pharmaceutical product, tautomer, hydrate, isomer, N-oxide, prodrug, polymorph, or any combination thereof, to treat, attenuate, reduce severity, risk reduction, delayed progression or suppression of CNS cancer, metastatic CNS cancer, refractory CNS cancer, or drug-resistant CNS cancer. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In some embodiments, the present invention provides the use of a compound described herein, or a metabolite, pharmaceutically acceptable salt, pharmaceutical product, tautomer, polymorph, hydrate, isomer, N-oxide, prodrug, or any combination thereof, to treat, attenuate, reduce the severity, risk reduction, or suppression of the cancer (s) tumor or drug-resistant tumors in the subject. In another embodiment, the cancer is adrenal cortex carcinoma, anal cancer, bladder cancer, brain tumor, brain stem tumor, breast cancer, drug-resistant breast cancer, glioma, cerebellar astrocytoma, cerebellar astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors of the pineal gland, hypothalamic glioma, carcinoid tumor, carcinoma, cervical cancer, colon cancer, central nervous system (CNS) cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's tumor family (Pnet), extracranial embryonic cell tumor, eye cancer, intraocular melanoma, gallbladder cancer, stomach cancer, embryonic cell tumor, extragonadal gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell carcinoma, laryngeal cancer, leukemia, acute lymphoblastic leukemia, oral cancer , liver cancer, lung cancer, non-small cell lung cancer, m aecellular lymphoma, AIDS-related lymphoma, (primary) central nervous system lymphoma, cutaneous T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, malignant mesothelioma, melanoma, drug-resistant melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma, multiple myeloma , neoplasms of plasma cells, fungal mycosis, myelodysplastic syndrome, myeloproliferative disorders, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, ovarian epithelium cancer, embryonic ovarian cell tumor, borderline ovarian tumor, pancreatic cancer, exocrine gland islet cell carcinoma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pheochromocytoma, pituitary cancer, plasma cell neoplasms, prostate cancer, rhabdomyosarcoma, rectal cancer, kidney cancer, renal cell carcinoma, salivary gland cancer, Sesari syndrome, skin cancer, to indigestion T-cell lymphoma, skin cancer, Kaposi's sarcoma, skin cancer, melanoma, drug-resistant melanoma, small bowel cancer, soft tissue sarcoma, testicular cancer, malignant thymoma, thyroid cancer, urethra cancer, uterine cancer, sarcoma, rare pediatric cancers, vaginal cancer, vulvar cancer, Wilms' tumor, or any combination thereof. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the tumor is prostate cancer. In another embodiment, the tumor is multidrug-resistant (MDR) prostate cancer. In another embodiment, the tumor is ovarian cancer. In another embodiment, the tumor is multidrug-resistant (MDR) ovarian cancer. In another embodiment, the tumor is uterine cancer. In another embodiment, the tumor is multidrug-resistant (MDR) uterine cancer. In another embodiment, the tumor is a melanoma tumor. In another embodiment, the tumor is a drug resistant melanoma tumor. In another embodiment, the tumor is a multidrug-resistant (MDR) melanoma tumor. In another embodiment, the tumor is lung cancer. In another embodiment, the tumor is colon cancer. In another embodiment, the tumor is breast cancer. In another embodiment, the tumor is a drug resistant breast cancer. In another embodiment, the tumor is a glial tumor. In another embodiment, the tumor is a leukemic tumor.

In one embodiment, the present invention relates to a method of destroying a cancer cell, comprising: providing a compound of the present invention and contacting the cancer cell with the compound under conditions that are effective to destroy the contacted cancer cell. In various embodiments, the destruction of cancer cells can be destroyed in vivo or ex vivo (ie, in culture). In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is compound 15. In another embodiment, the compound is compound 18. In another embodiment, the compound is compound 33. In another embodiment, the cancer is selected from the group consisting of prostate cancer, drug resistant prostate cancer , breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer, melanoma, drug-resistant melanoma, lung cancer, colon cancer, leukemia, glioma, kidney cancer, CNS cancer, uterine cancer, cancer uterus with medicinal nd resistance and combinations thereof.

In one embodiment, the present invention relates to a method for suppressing, preventing, or slowing the progression of tumor vascularization, comprising administering a compound of the present invention to a subject with cancer under conditions that are effective to suppress, prevent, or slow the progression of vascularization of said tumor. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In one embodiment, the present invention provides a method for suppressing, preventing, or slowing the progression of vascularization of a metastatic tumor, comprising administering a compound of the present invention to a subject with cancer under conditions that are effective to suppress, prevent, or slow the progression of vascularization of said tumor. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In another embodiment, the tumor is selected from the group consisting of prostate cancer, drug resistant prostate cancer, breast cancer, drug resistant breast cancer, glial tumor, ovarian cancer, drug resistant ovarian cancer, skin cancer , melanoma, drug-resistant melanoma, lung cancer, colon cancer, lymphoma, kidney cancer, CNS cancer, uterine cancer, drug-resistant uterine cancer, and combinations thereof.

An additional aspect of the present invention relates to a method for treating or preventing a cancerous condition, comprising: providing a compound of the present invention and then administering an effective amount of the compound to a patient using a method that is effective to treat or prevent a cancerous condition.

In one embodiment, the patient being treated has a precancerous condition, and administration of the compound is effective to prevent the precancerous condition from progressing to a cancerous condition. This prevention can occur by destroying the precancerous cell before its additional development to a cancerous state or simultaneously with it.

In another embodiment, the patient being treated is characterized by a cancerous state, and administration of the compound is effective to regress the cancerous state or suppress the development of a cancerous state, i. E. stopping its development or reducing the rate of development, which preferably occurs when cancer cells are destroyed regardless of their location in the patient's body, that is, cancer cells that are located in the primary site of the tumor, or cancer cells that have formed metastases and created secondary tumors in the patient's body.

As used herein, a subject or patient refers to any mammalian patient, including, but not limited to, humans and other primates, dogs, cats, horses, cows, sheep, pigs, rats, mice, and other rodents. In one embodiment, the subject is a human. In one embodiment, the subject is a male. In another implementation, the subject is a woman. In some embodiments, the methods described herein may be suitable for treating men or women.

Administration of the compounds of the present invention can be carried out systemically or alternatively directly to a specific site where cancer cells or precancerous cells are present. Thus, administration can be carried out by any method that is effective for delivering the compounds or pharmaceutical compositions to cancer cells or precancerous cells. Typical routes of administration include, without limitation, administration of the compounds or compositions by oral, topical, transdermal, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intranasal, intracavitary or intravesical, intraocular, intraarterial, intralesional, or membrane applications, such as those found in the nose, throat, and bronchial tubes.

The compounds of the present invention are suitable for the treatment or prevention of various forms of cancer, in particular prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer (e.g. melanoma), drug-resistant melanoma, lung cancer, colon cancer, glioma, leukemia, lymphoma, kidney cancer, uterine cancer, drug-resistant uterine cancer, and CNS cancer (eg, glioma, glioblastoma). In addition, given the mode of action as tubulin inhibitors, other cancers are likely to be treatable or preventable when the compounds or compositions of the present invention are administered to a patient. Preferred compounds of the present invention selectively destroy cancer cells, deplete cancer cells, but preferably non-normal cells. It is important to note that harm to normal cells is minimized since cancer cells are susceptible to destruction when using significantly lower concentrations of the compounds of the present invention.

The compounds of the present invention are suitable for the treatment, reduction of severity, risk reduction or suppression of cancer, metastatic cancer, refractory cancer or drug resistant cancer. In another embodiment, the cancer is prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, skin cancer (e.g., melanoma), drug-resistant melanoma, lung cancer, colon cancer, glioma, leukemia, lymphomas, head cancer and neck, pancreas, esophagus, kidney cancer, uterine cancer, or CNS cancer, or combinations thereof. Methods for the treatment of these various types of cancer are substantiated in the examples given in the present description. In addition, given the mode of action as tubulin inhibitors, other cancers are likely to be treatable or preventable when the compounds or compositions of the present invention are administered to a patient. Preferred compounds of the present invention selectively destroy cancer cells, deplete cancer cells, but preferably non-normal cells. It is important to note that harm to normal cells is minimized since cancer cells are susceptible to destruction when using significantly lower concentrations of the compounds of the present invention. In one embodiment, the compound is a compound of Formula I-XV. In another embodiment, the compound is Compound 4. In one embodiment, the compound is Compound 5. In another embodiment, the compound is Compound 6. In another embodiment, the compound is Compound 7. In another embodiment, the Compound is Compound 14 In another embodiment, the compound is Compound 15. In another embodiment, the compound is Compound 18. In another embodiment, the compound is Compound 33.

In one embodiment, the compound is administered in combination with an anti-cancer agent by administering the compounds described herein, alone or in combination with other agents. In one embodiment, the compound is administered in combination with other cancer therapy (such as radiotherapy, chemotherapy, biological therapy).

If the compounds or pharmaceutical compositions of the present invention are administered to treat, ameliorate, reduce the severity, reduce the risk, or suppress a cancerous condition, the pharmaceutical composition may also contain other therapeutic agents, or it can be used in conjunction with other treatment regimens currently known or those to be developed subsequently to treat various types of cancer. Examples of other therapeutic agents or treatment regimens include, but are not limited to, radiation therapy, immunotherapy, chemotherapy, surgery, and combinations thereof.

The following examples are provided to more fully illustrate embodiments of the invention. However, they should not be construed as limiting in any way the broad scope of the invention.

Examples of

Example 1

Synthesis of compounds of formula I (figure 2)

Materials. All reagents were purchased from Sigma-Aldrich Chemical Co., Fisher Scientific (Pittsburgh, PA, USA), AK Scientific (Mountain View, CA, USA), Oakwood Products (West Columbia, SC, USA), etc. and used without further purification. Moisture-sensitive interactions were carried out in an argon atmosphere. Typical thin layer chromatography (TLC) was performed on aluminum-backed Uniplates (Analtech, Newark, DE, USA). Melting points were measured using a Fisher-Johns melting point measuring device (uncorrected). NMR spectra were obtained on a Bruker AX 300 spectrometer (Billerica, MA, USA) or on a Varian Inova-500 spectrometer. Chemical shifts are expressed in parts per million (ppm) relative to TMS in CDCl ₃ . Mass spectrometry data were acquired on a Bruker ESQUIRE electron spray / ion trap device with positive and negative ion detection. Elemental analysis was performed at Atlantic Microlab Inc., (Norcross, GA, USA). Unless otherwise specified, all test compounds were> 95% pure by combustion analysis.

General method of obtaining compounds 3-7 (figure 2): Various aldehydes, 3-bromobenzene-1,2-diamine (3 mmol), p-toluenesulfonic acid (0.3 mmol) and 15 ml of EtOH were boiled under reflux for 24 hours in an argon atmosphere. The solvent was removed, 25 ml of water was added and the mixture was extracted with EtOAc (3 × 50 ml). The combined organic layers were dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to give the desired 4-bromo-2-substituent-1H-benzo [d] imidazole.

The corresponding bromides obtained in the previous step (1 eq.), 3,4,5-trimethoxyphenylboronic acid (1 eq.), Sodium carbonate solution (2 eq.) In a mixture of THF (3 ml) / water (0.3 ml ) and tetrakis (triphenylphosphine) palladium (0.1 eq.) were refluxed overnight. After adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over MgSO ₄ , filtered and concentrated in vacuo. The residue was purified by flash chromatography to provide the desired fused "D" ring benzimidazole compounds or imidazo [4,5-c] pyridine compound 7 (Figure 2).

2-phenyl-4- (3,4,5-trimethoxyphenyl) -1H-benzo [d] imidazole (3). ¹ H NMR (CDCl ₃ ): 3.78, 3.93 (s, s, 6H), 3.91, 3.98 (s, s, 3H), 6.10, 6.82 (s, s, 2H), 7.29-8.08 (m, 8H), 9.70, 9.84 (s, br, 1H). MS (ESI) m / z 359.1 [M-H] ^- , 361.4 [M + H] ⁺ . Analysis (C ₂₂ H ₂₀ N ₂ O ₃ ) C, H, N.

2- (1H-indol-3-yl) -4- (3,4,5-trimethoxyphenyl) -1H-benzo [d] imidazole (4). ¹ H NMR (DMSO-d ₆ ): 3.76, 3.97 (s, s, 3H), 3.90, 3.97 (s, s, 6H), 6.96-7.62 (m, H), 7.62, 7.72 (s, s, 2H), 8.16, 8.42 (s, br, 1H), 8.58, 8.66 (d, d, 1H), 11 , 57, 11.64 (s, s, 1H), 12.16, 12.60 (s, s, 1H). MS (ESI) m / z 398.1 [MH] ^- , 400.3 [M + H] ⁺ . Analysis (C ₂₄ H ₂₁ N ₃ O ₃ ) C, H, N.

2- (1H-indol-5-yl) -4- (3,4,5-trimethoxyphenyl) -1H-benzo [d] imidazole (5). ¹ H NMR (DMSO-d ₆ ): 3.73, 3.87 (s, s, 6H), 3.75, 3.92 (s, s, 3H), 5.70, 5.75 (s, s, 2H), 6.32, 6.49 (s, s, 1H), 6.54, 6.85 (d, d, 1H), 7.22-7.65 (m, 4H), 8, 01, 8.42 (br, s, 2H), 11.09, 11.37 (s, s, 1H), 12.36, 12.84 (s, s, 1H). MS (ESI) m / z 398.1 [MH] ^- , 400.1 [M + H] ⁺ . Analysis (C ₂₄ H ₂₁ N ₃ O ₃ ) C, H, N.

3- (4- (3,4,5-trimethoxyphenyl) -1H-benzo [d] imidazol-2-yl) -1H-indazole (6). ¹ H NMR (DMSO-d ₆ ): 3.76 (s, 3H), 3.95 (s, 6H), 6.65 (s, 1H), 6.93 (t, 1H), 7.34- 7.34 (m, 2H), 7.45-7.57 (m, 4H), 7.63 (s, 2H), 7.70 (d, 1H), 8.75 (d, 1H), 12 , 96 (s, 1H), 13.77 (s, 1H). MS (ESI) m / z 399.1 [M-H] ^- , 401.3 [M + H] ⁺ . Analysis (C ₂₃ H ₂₀ N ₄ O ₃ ) C, H, N.

2- (1H-indol-5-yl) -4- (3,4,5-trimethoxyphenyl) -1H-imidazo [4,5-c] pyridine (7). ¹ H NMR (DMSO-d ₆ ): 3.77 (s, 3H), 3.96 (s, 6H), 6.61 (s, 1H), 7.46-7.48 (m, 2H), 7.59 (d, 1H), 8.08 (dd, 1H), 8.36 (d, 1H), 8.41 (s, 2H), 8.49 (s, 1H), 11.44 (s , 1H), 13.26 (s, 1H). MS (ESI) m / z 399.0 [M-H] ^- , 401.3 [M + H] ⁺ . Analysis (C ₂₃ H ₂₀ N ₄ O ₃ ) C, H, N.

Example 2

Synthesis of compounds of formula XI (figure 3)

(4-hydroxy-3,5-dimethoxyphenyl) (2-phenylthiazol-4-yl) methanone (11).

Intermediates 8-10 were prepared from benzonitrile and cysteine according to the method described in Lu, Y .; Li, S.M .; Wang, Z .; Ross, C. R., 2nd; Chen, J .; Dalton, J. T .; Li, W .; Miller, DD Discovery of 4-substituted methoxybenzoyl-aryl-thiazole as novel anticancer agents: synthesis, biological evaluation, and structure-activity relationships. J Med Chem 2009, 52 (6), 1701-11. Compound 10 [matrix compound "SMART" (4-substituted methoxybenzoyl-aryl-thiazole)] (500 mg, 1.4 mmol) was dissolved in CH ₂ Cl ₂ (50 ml) at RT under a protective argon atmosphere. Anhydrous AlCl ₃ (374 mg, 2.8 mmol) was added and the reaction mixture was stirred for 12 hours. The reaction was quenched with H ₂ O (30 ml), the organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 20 ml). The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography using hexanes-EtOAc provided compound 11 (410 mg, 85.9% yield). ¹ H NMR (CDCl ₃ ): 4.00 (s, 6H), 6.02 (s, 1H), 7.47-7.48 (m, 3H), 7.91 (s, 2H), 8, 01-8.03 (m, 2H), 8.27 (s, 1H). MS (ESI) m / z 339.9 [M-H] ^- , 364.1 [M + Na] ⁺ . Analysis (C ₁₈ H ₁₅ NO ₄ S) C, H, N.

2,6-dimethoxy-4- (2-phenylthiazole-4-carbonyl) phenyl-2-chloroacetate (12). At 0 ° C into a solution of 11 (100 mg, 0.29 mmol) in CH ₂ Cl ₂ ; (30 ml) was added 2-chloroacetyl chloride (100 mg, 0.9 mmol). Then, triethylamine (44 mg, 0.44 mmol) was added to the mixture and stirred until the starting material disappeared from TLC analysis. The reaction was quenched with H ₂ O (10 ml), the organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 10 ml). The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography using hexanes-EtOAc provided compound 12 (99 mg, 81.7% yield). _Mp 147-148 ° C. ¹ H NMR (CDCl ₃ ): 3.92 (s, 6H), 4.42 (s, 2H), 7.47-7.49 (m, 3H), 7.82 (s, 2H), 8, 00-8.02 (m, 2H), 8.32 (s, 1H). MS (ESI) m / z 418.1 [M-H] ^- . Analysis (C ₂₀ H ₁₆ ClNO ₅ S) C, H, N.

2,6-dimethoxy-4- (2-phenylthiazole-4-carbonyl) phenyl-2,2,2-trifluoroacetate (13). At 0 ° C, trifluoroacetic anhydride (189 mg, 0.9 mmol) was added to a solution of 11 (100 mg, 0.29 mmol) in CH ₂ Cl _{2 (10 ml).} Then DMAP (54 mg, 0.44 mmol) was added to the mixture and stirred at RT until the starting material disappeared from TLC analysis. The reaction was quenched with H ₂ O (10 ml), the organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 10 ml). The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography using a hexanes-EtOAc system afforded compound 13 (89 mg, 70.2% yield). _Mp 151-153 ° C. ¹ H NMR (CDCl ₃ ): 3.94 (s, 6H), 7.48-7.49 (m, 3H), 7.84 (s, 2H), 8.00-8.02 (m, 2H ), 8.34 (s, 1H). MS (ESI) m / z 438.1 [M + H] ⁺ . Analysis (C ₂₀ H ₁₆₄ F ₃ NO ₅ S) C, H, N.

(4- (benzyloxy) -3,5-dimethoxyphenyl) (2-phenylthiazol-4-yl) methanone (14). In an argon atmosphere, potassium carbonate (49 mg, 0.352 mmol) and benzyl bromide (33 mg, 0.194 mmol) were added to a solution of 11 (60 mg, 0.176 mmol) in 10 ml of dry DMF. The mixture was stirred for 1 hour at 100 ° C, then poured into water (10 ml). Compound 14 was extracted with EtOAc, washed with distilled water, dried over magnesium sulfate and concentrated in vacuo on a rotary evaporator. The crude oily product was purified by flash column chromatography to give a white solid 14 (51 mg). Yield = 62.7%. _Mp 119-120 ° C. ¹ H NMR (CDCl ₃ ): 3.92 (s, 6H), 5.15 (s, 2H), 7.29-7.37 (m, 3H), 7.48-7.51 (m, 5H ), 7.79 (s, 2H), 8.01-8.02 (m, 2H), 8.28 (s, 1H). MS (ESI) m / z 432.1 [M + H] ⁺ . Analysis (C ₂₅ H ₂₁ NO ₄ S) C, H, N.

(3,5-dimethoxy-4- (methoxymethoxy) phenyl) (2-phenylthiazol-4-yl) methanone (15). At 0 ° C, MOMCl (27 mg, 0.33 mmol) was added to a solution of 11 (75 mg, 0.22 mmol) in CH ₂ Cl _{2 (10 ml).} Then the mixture was added with Hunig's base (57 mg, 0.44 mmol) and stirred at RT until the starting material disappeared from TLC analysis. The reaction was quenched with H ₂ O (10 ml), the organic phase was separated and the aqueous phase was extracted with CH ₂ Cl ₂ (2 × 10 ml). The combined organic phases were washed with brine, dried over MgSO ₄ , filtered and concentrated to dryness under reduced pressure. Purification by flash column chromatography using hexanes-EtOAc gave 15 (83 mg, 98.0% yield) as yellow crystals. _Mp 103-104 ° C. ¹ H NMR (CDCl ₃ ): 3.62 (s, 3H), 3.95 (s, 6H), 5.26 (s, 2H), 7.47-7.49 (m, 3H), 7, 80 (s, 2H), 8.01-8.03 (m, 2H), 8.28 (s, 1H). MS (ESI) m / z 408.1 [M + Na] ⁺ . Analysis (C ₂₀ H ₁₉ NO ₅ S) C, H, N.

2- (2- (2,6-dimethoxy-4- (2-phenylthiazole-4-carbonyl) phenoxy) ethyl) isoindoline-1,3-dione (17). K ₂ CO ₃ ( 97 mg, 0.7 mmol) and the reaction mixture was stirred at 120 ° C overnight. Then the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was concentrated and further purified by column chromatography to give 132 mg of pure target product 17. Yield = 43.5%. _Mp 148-150 ° C. ¹ H NMR (CDCl ₃ ) δ 3.71 (s, 6H), 4.14 (t, 2H, J = 5.5 Hz), 4.41 (t, 2H, J = 5.5 Hz), 7 , 49-7.51 (m, 3H), 7.70 (s, 2H), 7.75 (q, 2H, J = 3.0 Hz), 7.91 (q, 2H, J = 3.0 Hz), 8.01-8.03 (m, 2H), 8.27 (s, 1H). MS (ESI) m / z 537.1 [M + Na] ⁺ . Analysis (C ₂₈ H ₂₂ N ₂ O ₆ S) C, H, N.

(4- (2-aminoethyl) -3,5-dimethoxyphenyl) (2-phenylthiazol-4-yl) methanone (18). Cs ₂ CO ₃ (46 mg, 0.2 mmol) and the reaction mixture was stirred for 3 days at RT until TLC analysis indicated the reaction was complete. Then the reaction was quenched with ice water and the mixture was extracted with ethyl acetate. The organic layer was concentrated and further purified by column chromatography to obtain 22 mg of pure target product tert-butyl- (2- (2,6-dimethoxy-4- (2-phenylthiazole-4-carbonyl) phenoxy) ethyl) carbamate 16. Yield = 65.1%. MS (ESI) m / z 483.9 [M-H] ^- , 485.1 [M + H] ⁺ . The Boc-protected compound 16 was added to a solution of HCl in dioxane (4M) and stirred overnight. The precipitate was collected and washed with diethyl ether to give the HCl salt of compound 18. ¹ H NMR (acetone-d ₆ ): 3.09-3.13 (q, 2H, J = 5.5 Hz), 3.79 (br. 2H), 3.90 (s, 6H), 4.17 (t, 2H, J = 5.5 Hz), 7.55-7.58 (m, 3H), 7.66 (s, 2H), 8.02-8.04 (m, 2H), 8.68 (s, 1H). MS (ESI) m / z 385.1 [M + H] ⁺ . Analysis (C ₂₀ H ₂₀ N ₂ O ₃ S) C, H, N.

Example 3

Synthesis of phenyl-amino-thiazole / imidazole compounds (figure 4)

N-phenyl-1H-imidazol-2-amine (21). At 0 ° C, BrCN (2.11 g, 20 mmol) was added in small portions to a solution of aminoacetaldehyde diethyl acetal (2.66 g, 20 mmol) in diethyl ether / hexane (20 ml, 1: 1). The reaction mixture was stirred at RT overnight. Remove the solid by filtration and wash with diethyl ether. Concentrated the combined filtrate. Purification by flash column chromatography (silica gel, eluted with a gradient of dichloromethane then 5% methanol in dichloromethane) afforded N- (2,2-diethoxyethyl) carbodiimide 19. ¹ H NMR, 500 MHz (CDCl ₃ ): 1.23 (t, 6H, J = 7.0 Hz), 3.16 (t, 2H, J = 6.0 Hz), 3.56 (dt, 2H), 3.64 (br, s, 1H), 3.73 (dt, 2H), 4.58 (t, J = 5.0 Hz, 1H). MS (ESI) m / z 156.8 [M-H] ^- , 180.9 [M + Na] ⁺ . Aniline (1.66 g, 17.8 mmol) was dissolved in ethanol (50 ml) and a solution of 19 (2.82 g, 17.8 mmol) in 5 ml of diethyl ether was added dropwise. Then methanesulfonic acid (1.71 g, 17.8 mmol) was added and the mixture was refluxed for 24 hours. The reaction mixture was poured into NaOH (0.5M) and extracted with CH ₂ Cl ₂ . Drying with MgSO ₄ and concentration in vacuo gave the product, which was purified by flash chromatography to provide guanidine intermediate 20 (3.3 g, 73.8%). Guanidine (3 g, 12 mmol) was dissolved in HCl (5 ml, 6 M) at 0 ° C and then stirred for 2 hours. After consumption of the starting material, NaOH (25%) was added until a precipitate formed (pH 14). The resulting mixture was stirred for 30 minutes. Then the reaction mixture was poured into NaOH (0.5M), extracted with CH ₂ Cl ₂ , dried and concentrated. Purification by flash chromatography gave 21 (1.16 g, 61%). ¹ H NMR (DMSO-d ₆ ): 6.68 (s, 2H), 6.75 (m, 1H), 7.17 (m, 2H), 7.34 (m, 2H), 8.58 ( s, 1H). MS (ESI) m / z 157.6 [M-H] ^- , 160.0 [M + H] ⁺ .

3,4,5-trimethoxy-N-phenyl-N- (1- (phenylsulfonyl) -1H-imidazol-2-yl) benzamide (22). To a solution of N-phenyl-1H-imidazol-2-amine 21 (40 mg, 0.25 mmol) in CH ₂ Cl ₂ (10 mL) was added benzenesulfonyl chloride (441 mg, 2.5 mmol) and triethylamine (252 mg, 2 , 5 mmol). The reaction mixture was stirred overnight at room temperature. The reaction extinguished us. NH ₄ Cl and the mixture was extracted with CH ₂ Cl ₂ . Drying with MgSO ₄ and concentration in vacuo afforded the product, which was purified by flash chromatography to give the benzenesulfonyl-protected intermediate (79 mg, 72%). The resulting intermediate was dissolved in THF and cooled to -78 ° C, and then t-BuLi (1.7 M) was added under Ar. After stirring for another hour, 3,4,5-trimethoxybenzoyl chloride (47 mg, 0.26 mmol) was added and stirred overnight. The reaction mixture was poured into NH ₄ Cl (sat) and extracted with ethyl acetate. Drying with MgSO ₄ and concentration in vacuo gave the crude product, which was purified by flash chromatography to give 22 (35%). ¹ H NMR (CDCl ₃ ): 3.78 (s, 6H), 3.87 (s, 3H), 6.91 (s, 2H), 6.97 (s, 1H), 7.18 (m, 2H), 7.20 (d, 1H), 7.25 (m, 2H), 7.38 (m, 2H), 7.40 (d, 1H), 7.54 (br, 1H), 7 , 59 (t, 2H). MS (ESI) m / z 491.9 [M-H] ^- , 516.1 [M + Na] ⁺ .

N- (1H-imidazol-2-yl) -3,4,5-trimethoxy-N-phenylbenzamide (23). _{Boc 2} O (2.68 g, 12.3 mmol) was added to a solution of N-phenyl-1H-imidazol-2-amine 21 (900 mg, 5.66 mmol) in dioxane and water (30 ml, 3: 1) and NaOH (0.6 g, 15 mmol) and stirred for 4 hours. Concentrate the mixture in vacuo and purify the residue by flash chromatography to give the Boc-protected intermediate. The resulting intermediate (130 mg, 0.502 mmol) was dissolved in THF and cooled to -78 ° C, and then t-BuLi (0.65 ml, 1.7 M, 1.1 mmol) was added under Ar. After stirring for an hour, 3,4,5-trimethoxybenzoyl chloride (116 mg, 0.502 mmol) was added and stirred overnight. The reaction mixture was poured into NH ₄ Cl (sat) and extracted with ethyl acetate. Drying with MgSO ₄ and concentration in vacuo gave the crude product, which was purified by flash chromatography to give 23 (35%). ¹ H NMR (CDCl ₃ ): 3.65 (s, 6H), 3.79 (s, 3H), 6.56 (s, 2H), 6.90 (m, 2H), 7.27-7, 39 (m, 5H), 11.17 (br, 1H). MS (ESI) m / z 351.8 [M-H] ^- , 376.3 [M + Na] ⁺ .

N-phenyl-4-trityl-1H-imidazol-2-amine (24) and N-phenyl-1-trityl-1H-imidazol-2-amine (25). To a solution of N-phenyl-1H-imidazol-2-amine 21 (159 mg, 10 mmol) in triethylamine and CH ₂ Cl ₂ , which was stirred in an inert atmosphere at 0 ° C, (chloromethanetriyl) tribenzene (5 eq.) Was added. The solution was left to warm to RT and stirred until completion of the reaction according to TLC. The reaction mixture was then concentrated in vacuo, quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate, then dried with magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash chromatography to give two different protected products. 24: ¹ H NMR (DMSO-d ₆ ): 6.0 (s, 1H), 6.75 (m, 1H), 7.29-7.62 (m, 19H), 8.65 (s, 1H ), 10.62 (s, 1H). MS (ESI) m / z 399.9 [M-H] ^- , 403.1 [M + H] ⁺ . 25: ¹ H NMR (DMSO-d ₆ ): 6.08 (s, 1H), 6.41 (s, 1H), 6.85 (s, 1H), 7.13-7.52 (m, 20H ), 8.65 (s, 1H), 10.62 (s, 1H). MS (ESI) m / z 399.8 [MH] ^- , 402.8 [M + H] ⁺ .

(2- (phenylamino) -1-trityl-1H-imidazol-4-yl) (3,4,5-trimethoxyphenyl) methanone (26). T-BuLi (0, 34 ml, 1.7 M, 0.58 mmol) and trimethoxybenzoyl chloride (66.5 mg, 0.289 mmol). The reaction mixture was left to react overnight, then the reaction was quenched with NH ₄ Cl (sat.) And was extracted with ethyl acetate. Drying with MgSO ₄ and concentration in vacuo gave the crude product, which was purified by flash chromatography to give 26 (75 mg, 43.7%). ¹ H NMR (DMSO-d ₆ ): 3.71 (s, 3H), 3.78 (s, 6H), 5.87 (s, 1H), 6.94 (s, 2H), 7.18- 7.58 (m, 21H). MS (ESI) m / z 594.2 [M-H] ^- , 596.3 [M + H] ⁺ .

(2- (phenylamino) -1H-imidazol-4-yl) (3,4,5-trimethoxyphenyl) methanone (27). (2- (phenylamino) -1-trityl-1H-imidazol-4-yl) (3,4,5-trimethoxyphenyl) methanone was dissolved in a solution of HC1 in diethyl ether (2M) and stirred overnight. Then a saturated solution of NaHCO _{3 was} added and the reaction mixture was extracted three times with diethyl ether. Dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo. The residue was purified by flash chromatography to give the pure 27. ¹ H NMR (DMSO-d _6): 3,73 (s, 3H), 3,82 (s, 6H), 6,62 (s, 2H), 7, 02 (s, 2H), 7.33 (d, 2H), 7.43-7.51 (m, 3H), 7.54 (br, 1H). MS (ESI) m / z 352.1 [M-H] ^- , 354.3 [M + H] ⁺ . Analysis (C ₁₉ H ₁₉ N ₃ O ₄ ) C, H, N.

N - ((1H-indol-5-yl) carbamothioyl) benzamide (28). A mixture of 5-nitro-1H-indole (11 g, 67.9 mmol) and Pd / C (5%; 1 g), dissolved in ethanol (50 ml), was hydrogenated for 3 hours at 40 psi (280 kPa). Filtered the reaction mixture and evaporated excess ethanol under reduced pressure. The solid product was recrystallized from hexane to give the pure 5-aminoindole compound. Yield: 92.5%. ¹ H NMR (500 MHz, CDCl ₃ ): δ 3.50 (s, 2H), 6.37 (s, 1H), 6.67 (dd, 1H), 6.95 (s, 1H), 7, 13 (s, 1H), 7.20 (d, 1H), 7.96 (br, 1H). MS (ESI) m / z 133.0 (M + H) ⁺ . A solution of 5-aminoindole (8 g, 60.6 mmol) in acetone (150 ml) was reacted with benzoyl isothiocyanate (9.88 g, 60 mmol) at RT for about 4 hours until TLC analysis indicated complete interaction, was prepared compound 28. ¹ H NMR (300 MHz, CDCl _3): δ 6,61 (br s, 1H.), 7,26-7,28 (d , 1H), 7,38-7,45 (m , 2H), 7.54-7.59 (m, 2H), 7.65-7.70 (m, 1H), 7.91-7.94 (m, 2H), 7.98 (s, 1H ), 8.27 (s, br, 1H), 9.12 (s, 1H), 12.51 (s, 1H). MS (ESI) m / z 318.1 [M + Na] ⁺ .

2- (1H-indol-5-ylamino) -N-methoxy-N-methylthiazole-4-carboxamide (32). The resulting compound 28 was filtered off as a solid and treated with 2N. NaOH in THF (120 ml). The mixture was boiled under reflux for about 6 hours and left to warm to RT. The solvent was evaporated in vacuo. The residue was diluted with water (20 ml) and neutralized to pH 7 with 1N. HCl. The resulting solid was filtered off and dried in vacuo to give 5-indolylthiourea (29). Compound 29 (0.01 mol) and ethyl bromopyruvate (0.011 mol) were dissolved in 3 ml of ethanol and kept at the reflux temperature for 2 hours. The reaction mixture was cooled, crystalline ethyl 2- (1H-indol-5-ylamino) thiazole-4-carboxylate (30) was collected by filtration and washed with ethanol. Refluxing a mixture of ethyl esters with a NaOH-ethanol solution at the reflux temperature gave 2- (1H-indol-5-ylamino) thiazole-4-carboxylic acid (31), which was used directly in the next steps. To a mixture of crude acid (2.5 mmol), HBTU (2.6 mmol) and NMM (5.3 mmol) in CH ₂ Cl ₂ (30 ml) was added the HCl salt HNCH ₃ OCH ₃ (2.6 mmol) and continued stir at RT overnight. The reaction mixture was diluted with CH ₂ Cl ₂ (20 ml) and washed sequentially with water, sat. NaHCO ₃ , brine and dried over MgSO ₄ . The solvent was removed under reduced pressure to give a crude product that was purified by column chromatography to give pure Weinreb amide 2- (1H-indol-5-ylamino) -N-methoxy-N-methylthiazole-4-carboxamide (32) (overall yield 45 , 6% for 5 stages). ¹ H NMR (CDCl ₃ ): 3.42 (s, 3H), 3.77 (s, 3H), 6.54 (m, 1H), 7.26 (m, 1H), 7.29 (m, 2H), 7.40 (d, 2H), 7.61 (m, 1H), 8.30 (br, 1H). MS (ESI) m / z 303.0 [M + H] ⁺ .

(2 - ((1H-indol-5-yl) amino) thiazol-4-yl) (3,4,5-trimethoxyphenyl) methanone (33). At -78 ° C, n-BuLi in hexane (2.5N, 2.4 ml, 6 mmol ) in a protective atmosphere of Ar and stirred for 10 minutes. Weinreb amide 32 (1 mmol) in 10 ml THF was added to the lithium-containing reagent and left stirring at RT for 2 hours. The reaction extinguished us. NH ₄ Cl, the mixture was extracted with diethyl ether, dried with MgSO ₄ . The solvent was removed under reduced pressure to give a crude product which was purified by column chromatography to give pure 33 (51.7% yield). ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.89 (s, 6H), 3.93 (s, 3H), 6.55 (m, 1H), 7.15-7.12 (m, 1H) , 7.28-7.26 (m, 1H), 7.36 (s, 1H), 7.39 (s, 1H), 7.46 (s, 2H), 7.68 (d, 1H), 8.29 (br. 1H). MS (ESI) m / z 432.1 (M + Na) ⁺ , 408.0 (M-H) ^- . Analysis (C ₂₃ H ₁₉ N ₃ O ₄ S) C, H, N.

Example 4

Molecular Modeling of Compounds of the Present Invention Molecular Modeling. Molecular modeling studies were performed using the published crystal structures of the complex of α, β-tubulin dimer with DAMA-colchicine (protein databank code 1SA0). The modeling studies used the Schrödinger Molecular Modeling Kit (Schrodinger Inc., Portland, OR) using procedures similar to those previously described in Chen, J. et al. Bioorg Med Chem 2011,19 (16), 4782-95; Slominski, A.T. et al. The Journal of Steroid Biochemistry and Molecular Biology 2013, 137, 107-23; Xiao, M et al. J Med Chem 2013, 56 (8), 3318-29; Chen, J. et al. J Med Chem 2012,55 (16), 7285-9. Briefly, the structures of the protein-ligand complexes were obtained using the Protein Preparation module and the active ligand binding sites were determined from the data for the natural ligand. The structures of the natural ligand DAMA-colchicine and the proposed tubulin inhibitors described in this study were created and prepared for docking using the Ligprep (Ligand Preparation) module, followed by docking in 1SA0. The Glidescore docking index obtained in this modeling method is an estimated binding energy (kcal / mol) when the ligand binds to the tubulin dimer. A lower (more negative) value indicates more favorable binding between the ligand and the receptor. Data analysis was performed using the Maestro interface included in the software.

Compounds 4 and 7 were docked at the colchicine binding site in tubulin (Figure 6, PDB code: 1SA0) and were shown to have a very similar binding arrangement that overlaps well with the natural ligand. As expected, the trimethoxy fragment at 4 or 7 occupied the pocket of the trimethoxy fragment of the natural ligand (DAMA-colchicine), but some displacement of its location was observed. As a result of this slight displacement, the oxygen atoms of two methoxy groups in 4 and 7 were located close to Cys-241 in the β-subunit and provided the formation of two hydrogen bonds (dashed lines). NH in the imidazole moiety in 4 or 7 formed another hydrogen bond with Thr-179 in the α-subunit, as shown in Figure 6. It is interesting to note that due to the formation of a flat structure in the middle part of 4 or 7, the 5-indolyl moiety changed its orientation in such a way way to reach GTP in the α-subunit. Glidescore docking indices for 4 (-8.58) and 7 (-8.10) were comparable to the natural ligand, DAMA-colchicine (-9.26), according to these model calculations, this suggests that they have a comparable effect when binding of tubulin.

Example 5

Activity of the Compounds of the Present Invention Against Prostate Cancer and Melanoma

Cell culture and cytotoxicity study of prostate cancer and melanoma. All cell lines were obtained from ATCC (American Type Culture Collection, Manassas, VA, USA), while food sources for cell cultures were purchased from Cellgro Mediatech (Herndon, VA, USA). The authors of the present invention investigated the antiproliferative activity of the proposed anti-tubulin compounds against four human prostate cancer cell lines (LNCaP, DU 145, PC-3 and PPC-1) and three melanoma cell lines (A375, B16-F1 and WM-164). All prostate cancer cell lines were grown in RPMI 1640 supplemented with 10% fetal bovine serum (FBS). Melanoma cells were grown in DMEM supplemented with 5% FBS, 1% antibiotic / antifungal agent (Sigma-Aldrich, Inc., St. Louis, MO, USA) and bovine insulin (5 μg / ml; Sigma-Aldrich). The cytotoxic potential of anti-tubulin compounds was assessed using the sulforhodamine B (SRB) assay after 96 hours of treatment.

Results:

By comparing proliferative activity data with compound 10, which is an unsubstituted SMART matrix compound, most benzo-imidazoles 3-6 had only moderate activity; with the exception of 4, which contains 5-indolyl as ring substituent A, which had similar activity against the investigated melanoma and prostate cancer cell lines (see table 1). For further modification, 5-indolyl was retained as ring A and imidazole fused with pyridine was used as a substitute for benzoimidazole to give compound 7. This compound had increased activity over 10 and 4. IC ₅₀ values improved by at least 5 times against melanoma A375 cells and androgen-susceptible prostate cancer LNCaP cells. In addition, these new condensed ring matrices blocked possible phase I metabolic reactions mediated by ketone reduction at 10 (example 6).

Compound 15 had improved activity over trimethoxybenzoyl compound 10 (i.e. 20 nM (15) versus 28 nM (10) for A375 cells; Table 2). This discovery supported the suggestion that “the ara position of the benzoyl ring is a suitable site for further modification. An increase in the chain by two atoms (-OCH ₂ -) by 15 resulted in a compound that retained high activity. However, the idea of para-alkylation did not work as expected in suppressing cancer cell growth. According to the results shown in Table 2, it can be seen that the activity of the alkylating agent 12 against melanoma and prostate cancer cells was significantly reduced. Compounds 13 and 14 had similar trends in the activity change as did 12. 17, containing a phthalimide protecting group, exhibited activity in the micromolar range. Introduction ethylamine (18) in the para position retained reasonable activity, where IC ₅₀ value is in the range of hundreds of nanomoles, but were less active compared with compound 10 trimetoksibenzoilnym.

Table 3 shows the results for analogs of compounds, where 27 did not show any activity against all tested cell lines. 33 provided excellent in vitro suppression of prostate cancer and melanoma cell growth. IC ₅₀ values for prostate cancer cells were improved 2 to 3 times compared to PAT.

Molecular modeling studies of compound 33 (figure 7) showed the interaction between the specified ligand and the α, β-dimer of tubulin through three hydrogen bonds, similar to the interaction of 4 or 7 with tubulin. However, it can be seen that the 5-indolyl moiety in compound 33 did not reach the GTP moiety, as in case 4 or 7, which is possibly due to the fact that the ketone moiety is not close to the ring system as shown for 4 or 7. Thus , 33, mainly remains in the β-subunit of the tubulin dimer and has a significantly better Glidescore docking index (-8.70).

Example 6

Metabolic stability studies

Microsomal stability study. Studies of metabolic stability were carried out by incubating the test compounds (0.5 μM) in a reaction mixture with a total volume of 1.2 ml containing 1 mg / ml microsomal protein in a reaction buffer [0.2 M phosphate buffer solution (pH 7.4), 1 , 3 mM NADP ⁺ , 3.3 mM glucose-6-phosphate and 0.4 U / ml glucose-6-phosphate dehydrogenase], at 37 ° C in a shaker-incubator. Pooled human liver microsomes were used to assess metabolic stability. The NADPH regeneration system (solution A and B) was obtained from Xenotech, LLC (Lenexa, KS, USA). Aliquots (100 μl) of reaction mixtures for determination of metabolic stability were taken after 5, 10, 20, 30, 60 and 90 minutes. Acetonitrile (200 μL) containing 200 nM internal standard was added to quench the reaction and precipitate proteins. The samples were then centrifuged at 10,000 rpm for 15 minutes at RT and direct analysis of the supernatant was performed by LC-MS / MS (AB Sciex API4500). To identify metabolites, the reaction mixture was incubated for 2 hours together with the test compound at 50 μM concentration under the conditions described above. The supernatant was analyzed on a Water Xevo G2-S high resolution mass spectrometer.

In vitro metabolic stability studies. To determine the possibility of reducing the metabolism of the labile carbonyl linker by incorporating it into the cyclic structure, we measured metabolic stability in liver microsomes using two highly active compounds (4 and 7). The carbonyl linker at 10, which was susceptible to ketone reduction, was replaced with a ring. This modification ensured the retention of efficacy and at the same time improved metabolic stability by about 2-3 times (17 minutes versus 45 and 51 minutes for human liver microsomes, table 4) versus 10.

In addition, compounds 4 and 7 had increased activity. The metabolic stability of another active analogue 15, containing an increased MOM terminal group at the para-position of the benzoyl ring, was not improved for any of the liver microsomes studied. Another substituent, aminoethyl at 18, also located in the para position relative to O, blocked the tendency to metabolism at the benzoyl ring (T _1/2 ranged from 110 to 225 minutes for the studied types of liver microsomes). The result obtained confirmed that the para-position of the benzoyl ring can be a site, the modification of which can lead to an improvement in the stability of the compound.

Metabolic pathways of compounds 4, 7, 15 and 18 in vitro. To find out the reason why these new analogs had different metabolic profiles in liver microsomes, additional experiments were performed using a higher concentration (50 μM) of the test compounds. The inventors used a high-resolution mass spectrometer to identify metabolites where the measured mass error was generally less than 2 ppm. Detailed information regarding the mass spectra and chromatography of each of the metabolites is provided in the supplementary materials. In case 15 (Figure 8), the removal of the MOM group with the formation of M1 (identified by the mass spectrum 342.08 [M + 1]) is the main metabolic pathway, then O-demethylation of the 3'- or 5'-methoxy group occurs with the formation of M2 (which was identified by mass spectrum 328.06 [M + 1]). This result was consistent with the short half-life (<10 minutes) of the compound, as the MOM group is believed to be unstable after exposure to liver microsomes. M3 (which was identified by mass spectrum 372.09 [M + 1]) was also a product of O-demethylation, however, the exact site of this demethylation was not determined due to the limited information available at this stage. M4 (which was identified by the mass spectrum 388.12 [M + 1]) was a ketone reduction product, then it was hydroxylated to M5 (which was identified by the mass spectrum 404.12 [M + 1]) at a position that is impossible was determined due to limited information. In case 18 (Figure 9), the main metabolites are M6 (dealkylation) (identified by mass spectrum 342.08 [M + 1]) and M8 (ketone reduction) (identified by mass spectrum 387.14 [M + 1 ]). M7 (deamination) (identified by mass spectrum 370.11 [M + 1]) is a minor product. In case 4 (Figure 10), the main products were (9-demethylation (M9) and monohydroxylation (M10). M9 (which was identified by the mass spectrum 386.15 [M + 1]) and M10 (which was identified by the mass spectrum 416 , 16 [M + 1]) had more than one possible structure as indicated by the chromatograms In case 7 (Figure 11), various metabolites were detected, including demethylation products (M12) (identified by mass spectrum 387.15 [M + 1 ]), mono-hydroxylation (M14) (which was identified by the mass spectrum 417.16 [M + 1]), O-demethylation and subsequent mono-hydroxylation (M11) (which was identified by the mass spectrum 403.14 [M + 1]) and dihydroxylation (M13) (which was identified by the mass spectrum 433.15 [M + 1]). These products formed uniformly in similar relative amounts, and all these metabolites had several isomeric forms, as indicated on the chromatograms.

Example 7

Inhibition of tubulin polymerization

Investigation of tubulin polymerization in vitro. Bovine tubulin (0.4 mg, purity> 97%) (Cytoskeleton, Denver, CO, USA) was mixed with 10 μM test compound and incubated in 100 μl of universal tubulin buffer (80 mM PIPES, 2.0 mM MgCl ₂ , 0 , 5 mM EGTA and 1 mM GTP) with a pH of 6.9. Absorbance at 340 nm was monitored every minute for 20 minutes on a SYNERGY 4 Microplate Reader (Bio-Tek Instruments, Winooski, VT, USA). The spectrophotometer was set at 37 ° C to polymerize tubulin.

The compounds inhibit tubulin polymerization in vitro. The inhibition of tubulin polymerization was investigated using selected highly active compounds 4 and 7 with improved metabolic properties and compared with a positive control with colchicine and a negative control with taxol. DMSO was used as a blank control. Bovine tubulin (purity> 97%) was incubated with individual compounds (5 or 10 μM) to study their effect on tubulin polymerization (Figure 12). After 20 minutes incubation, compound 4 at 5 and 10 μM inhibited tubulin polymerization by 30% and 60%, respectively (Figure 12A) compared to the vehicle. At the same time, for compound 7 at a concentration of 5 and 10 μM, 33% and 81% inhibition were observed, respectively (Figure 12B). Compounds 4 and 7 both provided stronger inhibition than colchicine at the two concentrations tested. The data obtained allowed us to assume that these compounds have a high activity of inhibiting tubulin polymerization, which is in good agreement with their cytotoxicity.

All features described in this application (including the appended claims, abstract and any drawings) and / or all steps of any method or process thus disclosed may be combined with any of the above aspects in any combination except combinations where at least some of these features and / or stages are mutually exclusive. Despite the fact that the present application reflects and describes in detail the preferred embodiments, it should be understood by those skilled in the related art that various modifications, additions, substitutions, etc. are possible without departing from the spirit of the invention, which, accordingly, are considered to be within the scope of the invention defined by the following claims.

Claims (39)

1. The compound represented by formula II:

where Q is NH; Z is CH or N; A is phenyl, indolyl, or indazolyl, each of which is optionally substituted with at least one of the following: C ₁ -C ₅ linear or branched alkyl, or a combination thereof; R _{1 is} independently hydrogen, O- (C ₁ -C ₅ ) alkyl, O-halo (C ₁ -C ₅ ) alkyl, halo (C ₁ -C ₅ ) alkyl, -O (CH ₂ ) _j OCH ₃ , -O (CH ₂ ) _j NHCH ₃ , -O (CH ₂ ) _j NH ₂ , -O- (CH ₂ ) _j N (CH ₃ ) ₂ , - OC (O) CF ₃ , -OC (O) CH ₂ Cl, —OCH ₂ Ph, —O (CH ₂ ) _j N-phthalimide, or a combination thereof; R ₂ is hydrogen, O- (C ₁ -C ₅ ) alkyl, O-halo (C ₁ -C ₅ ) alkyl, F, Cl, Br, I, halo (C ₁ -C ₅ ) alkyl, CN, NO ₂ , -CH ₂ CN, NH ₂ , hydroxyl, COOH, C (O) H, NHCO- (C ₁ -C ₅ ) alkyl, -O (CH ₂ ) _k OCH ₃ , -O (CH ₂ ) _k OH, -O (CH ₂ ) _k NHCH ₃ , -O (CH ₂ ) _k NH ₂ , -O- (CH ₂ ) _k N (CH ₃ ) ₂ , -OC (O) CF ₃ , - OC (O) CH ₂ Cl, —OCH ₂ Ph or —O (CH ₂ ) _k N-phthalimide; j and k are independently integers from 1 to 5; n is an integer from 1 to 4; or a hydrate thereof, a pharmaceutically acceptable salt, or a combination thereof. 2. A compound according to claim 1, wherein said indolyl group is selected from:

,

,

or

, where said indolyl is substituted or unsubstituted. 3. A compound according to claim 1, wherein said indazolyl group is selected from:

,

or

, where the specified indazolyl group is substituted or unsubstituted. 4. A compound according to claim 1, wherein Z is CH. 5. A compound according to claim 1, wherein Z is N. 6. A compound according to claim 1, wherein R ₁ is OCH ₃ , n is 3 and R ₂ is hydrogen. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is compound 3 represented by the structure:

... 8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound is compound 4, 5, 6 or 7:

;

;

or

... 9. A pharmaceutical composition having anticancer activity and containing a compound according to claim 1 or a pharmaceutically acceptable salt thereof in an amount therapeutically effective for treating cancer, and at least one pharmaceutically acceptable carrier. 10. The pharmaceutical composition of claim 9, further comprising at least one pharmaceutically active compound suitable for the treatment of cancer. 11. A method of treating, ameliorating, reducing the severity, reducing the risk of developing or suppressing cancer, comprising administering a compound of claim 1 to a subject suffering from cancer under conditions effective to treat said cancer. 12. The method of claim 11, wherein said cancer is selected from the group consisting of prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, ovarian cancer, drug-resistant ovarian cancer, skin cancer, melanoma, drug-resistant melanoma, lung cancer, colon cancer, glioma, leukemia, lymphoma, kidney cancer, CNS cancer, uterine cancer, drug-resistant uterine cancer, and combinations thereof. 13. The method of claim 11, wherein said cancer is melanoma. 14. The method of claim 11, wherein said cancer is metastatic melanoma. 15. The method of claim 11, wherein said cancer is prostate cancer. 16. The method of claim 15, wherein said prostate cancer is drug resistant prostate cancer. 17. The method according to claim 11, characterized in that said administration is carried out in combination with other anticancer therapy. 18. A method of treating drug resistant tumor or tumors, comprising administering a compound of claim 1 to a subject suffering from cancer under conditions effective to treat said drug resistant tumor or tumors. 19. The method of claim 18, wherein said tumor is selected from the group consisting of prostate cancer, drug-resistant prostate cancer, breast cancer, drug-resistant breast cancer, glial tumor, ovarian cancer, cancer drug-resistant ovarian tumor, skin cancer, melanoma, drug-resistant melanoma, lung cancer, colon cancer, leukemia, lymphoma, kidney cancer, CNS cancer, uterine cancer, uterine cancer with drug resistant and combinations thereof. 20. The method of claim 18, wherein said tumor is a melanoma tumor. 21. The method of claim 18, wherein said tumor is a metastatic melanoma tumor. 22. The method of claim 18, wherein said tumor is prostate cancer. 23. The method according to claim 18, wherein said administration is carried out in combination with other anticancer therapy.

Images